Gap junction: Difference between revisions

Gap junction
Gap junction
	Gap junction
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MeSH	D017629
TH	H1.00.01.1.02024
FMA	67423
	Anatomical terminology [edit on Wikidata]

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A gap junction or nexus is a specialized intercellular connection between a multitude of animal cell-types.^[1]^[2]^[3] It directly connects the cytoplasm of two cells, which allows various molecules and ions to pass freely between cells.^[4]^[5]

One gap junction channel is composed of two connexons (or hemichannels) which connect across the intercellular space.^[4]^[5]^[6] Gap junctions are analogous to the plasmodesmata that join plant cells.^[7]

Structure

In vertebrates, gap junction hemichannels are primarily homo- or hetero-hexamers of connexin proteins. Invertebrate gap junctions comprise proteins from the hypothetical innexin family. However, the recently characterized pannexin family, which was originally thought to form intercellular channels (based on similar amino acid sequence similarity to innexins), in fact functions as single-membrane channels that communicate with the extracellular environment, and have been shown to pass calcium and ATP.

At gap junctions, the intercellular space is 4 nm^[6] and unit connexons in the membrane of each cell are lined up with one another.^[8]

Gap junction channels formed from two identical hemichannels are called homotypic, while those with differing hemichannels are heterotypic. In turn, hemichannels of uniform connexin composition are called homomeric, while those with differing connexins are heteromeric. Channel composition is thought to influence the function of gap junction channels.

Generally, the genes coding for gap junction channels are classified in one of three groups, based on sequence similarity: A, B and C (for example, GJA1, GJC1). However, genes do not code directly for the expression of gap junction channels; genes can only produce the proteins which make up gap junction channels (connexins). An alternative naming system based on this protein's molecular weight is also popular (for example: connexin43, connexin30.3).

Levels of organization

DNA to RNA to Connexin protein.
One connexin protein has four transmembrane domains
6 Connexins create one Connexon (hemichannel). When different connexins join together to form one connexon, it is called a heteromeric connexon
Two hemichannels, joined together across a cell membrane comprise a Gap Junction channel.
When two identical connexons come together to form a Gap junction channel, it is called a homotypic GJ channel. When one homomeric connexon and one heteromeric connexon come together, it is called a heterotypic gap junction channel. When two heteromeric connexons join, it is also called a heteromeric Gap Junction channel.
Several gap junction channels (hundreds) assemble within a macromolecular complex called a gap junction plaque.

Properties of connexon channel pairs

Allows for direct electrical communication between cells, although different connexin subunits can impart different single channel conductances, from about 30 pS to 500 pS.
Allows for chemical communication between cells, through the transmission of small second messengers, such as inositol triphosphate (IP₃) and calcium (Ca²⁺),^[7] although different connexin subunits can impart different selectivity for particular small molecules.
Generally allows transmembrane movement of molecules smaller than 485 Daltons^[10] (1,100 Daltons through invertebrate gap junctions^[11]), although different connexin subunits may impart different pore sizes and different charge selectivity. Large biomolecules, for example, nucleic acid and protein, are precluded from cytoplasmic transfer between cells through gap junction connexin channels.
Ensures that molecules and current passing through the gap junction do not leak into the intercellular space.

To date, five different functions have been ascribed to gap junction protein: a) electrical and metabolic coupling between cells b) Electrical and metabolic exchange through hemichannels c) Tumor suppressor genes (Cx43, Cx32 and Cx36) d) Adhesive function independent of conductive gap junction channel (neural migration in neocortex) e) Role of carboxyl-terminal in signaling cytoplasmic pathways (Cx43)

Occurrence and Distribution

Gap Junctions have been observed in various animal organs and tissues where cells contact each other. From the 1950s to 1970s they were detected in crayfish nerves,^[12] rat pancreas, liver, adrenal cortex, epididymis, duodenum, muscle,^[13] Daphnia hepatic caecum,^[14] Hydra muscle,^[15] monkey retina,^[16] rabbit cornea,^[17] fish blastoderm,^[18] frog embryos,^[19] rabbit ovary,^[20] re-aggregating cells,^[21]^[22] cockroach hemocyte capsules,^[23] rabbit skin,^[24] chick embryos,^[25] human islet of Langerhans,^[26] goldfish and hamster pressure sensing acoustico-vestibular receptors,^[27] lamprey and tunicate heart,^[28]^[29] rat seminiferous tubules,^[30] myometrium,^[31] eye lens ^[32] and cephalopod digestive epithelium.^[33] Since the 1970s gap junctions have continued to been found in nearly all animal cells that touch each other. By the 1990s new technology such as confocal microscopy allowed more rapid survey of large areas of tissue. Since the 1970s even tissues that were traditionally considered to possibly have isolated cells such as bone showed that the cells were still connected with gap junctions, however tenuously.^[34] Gap junctions appear to be in all animal organs and tissues and it will be interesting to find exceptions to this other than cells not normally in contact with neighboring cells. Adult skeletal muscle is a possible exception. It may be argued that if present in skeletal muscle gap junctions might propagate contractions in an arbitrary way among cells making up the muscle. At least in some cases this may not be the case as shown in other muscle types that do have gap junctions.^[35] An indication of what results from reduction or absence of gap junctions may be indicated by analysis of cancers ^[36]^[37]^[38] or the aging process.^[39]

Functions

The section "Areas of Electrical Coupling" reflects the circumstances of earliest discovery of gap junctions and their function in allowing the transmission of electrical impulses among cells at levels that elicit responses from their neighboring cells. The transmission of a nerve impulse and the contraction of muscle are relatively easily detected and quantified experimentally. "Areas of Electrical Coupling" also touches upon the retinal gap junctions which could be seen as specialist nerve cells. Many new functions for gap junctions have been uncovered since those early years.

Embryonic, Organ and Tissue Development

In the 1980s more subtle but no less important roles of gap junction communication have been investigated. It was discovered that gap junction communication could be disrupted by adding anti-connexin antibodies into embryonic cells.^[40]^[41] Embryos with areas of blocked gap junctions failed to develop normally. The mechanism by which antibodies blocked the gap junctions was unclear but systematic studies were undertaken to elucidate the mechanism.^[42]^[43] Refinement of these studies showed that gap junctions appeared to be key to development of cell polarity ^[44] and the left/right symmetry/asymmetry in animals.^[45]^[46] While signaling that determines the position of body organs appears to rely on gap junctions so does the more fundamental differentiation of cells at later stages of embryonic development.^[47]^[48]^[49]^[50]^[51] Gap junctions were also found to be responsible for the transmission of signals required for drugs to have an effect ^[52] and conversely some drugs were shown to block gap junction channels.^[53]

Gap junctions and the "bystander effect"

Cell death

The "bystander effect" with its connotations of the innocent bystander being killed is also mediated by gap junctions. When cells are compromised due to disease or injury and start to die messages are transmitted to neighboring cells connected to the dying cell by gap junctions. This can cause the otherwise unaffected healthy bystander cells to also die.^[54] The bystander effect is therefore important to consider in diseased cells which opened an avenue for more funding and a flourish of research.^[55]^[56]^[57]^[58]^[59]^[60]^[61]^[62]^[63] Later the bystander effect was also researched with regard to cells damaged by radiation or mechanical injury and therefore wound healing.^[64]^[65]^[66]^[67]^[68] Disease also seems to have an effect on the ability of gap junctions to fulfill their roles in wound healing.^[69]^[70]

Tissue restructuring

While there has been a tendency to focus on the bystander effect in disease due to the possibility of therapeutic avenues there is evidence that there is a more central role in normal development of tissues. Death of some cells and their surrounding matrix may be required for a tissue to reach its final configuration and gap junctions also appear essential to this process.^[71]^[72] There are also more complex studies that try and combine our understanding of the simultaneous roles of gap junctions in both wound healing and tissue development.^[73]^[74]

Areas of electrical coupling

Gap junctions electrically and chemically couple cells throughout the body of most animals. Electrical coupling can be relatively fast acting. Tissues in this section have well known functions observed to be coordinated by gap junctions with inter-cellular signaling happening in time frames of micro-seconds or less.

Heart

Gap junctions are particularly important in cardiac muscle: the signal to contract is passed efficiently through gap junctions, allowing the heart muscle cells to contract in tandem. Gap junctions are expressed in virtually all tissues of the body, with the exception of adult fully developed skeletal muscle and mobile cell types such as sperm or erythrocytes. Several human genetic disorders are associated with mutations in gap junction genes. Many of those affect the skin because this tissue is heavily dependent upon gap junction communication for the regulation of differentiation and proliferation.

Neurons

A gap junction located in neurons is often referred to as an electrical synapse. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. Few locations have been discovered where there is significant coupling between neurons in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the vestibular nucleus, the nucleus of trigeminal nerve, the inferior olivary nucleus, and the Ventral Tegmental Area. There has been some observation of weak neuron to glial cell coupling in the locus coeruleus, and in the cerebellum between Purkinje neurons and Bergmann glial cells. It appears that astrocytes are coupled by gap junctions, both to other astrocytes and to oligodendrocytes.^[75] Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in Pelizaeus-Merzbacher disease and multiple sclerosis.

Connexin proteins expressed in neuronal gap junctions include:

mCX36
mCX57
mCX45

with mRNAs for at least five other connexins (mCx26, mCx30.2, mCx32, mCx43, mCx47) detected but without immunocytochemical evidence for the corresponding protein within ultrastructurally-defined gap junctions. Those mRNAs appear to be down-regulated or destroyed by micro interfering RNAs ( miRNAs ) that are cell-type and cell-lineage specific.

Retina

Neurons within the retina show extensive coupling, both within populations of one cell type, and between different cell types.

Discovery

Where did the name come from?

Gap junctions were so named because of the "gap" shown to be present at these special junctions between two cells.^[76] With the increased resolution of the transmission electron microscope (TEM) gap junction structures were first able to be seen and described in around 1953.

Annular gap junction cross section in TEM thin section. Gap junctions are usually linear rather than annular in TEM thin sections. It is thought that annular gap junctions result from engulfment by one of the two cells of the membrane plaque to form a vesicle within the cell. This example shows three layers to the junction structure. The membrane from each cell is the dark line with the whiter narrow gap between the two darkly stained membranes. In such electron micrographs there may appear to be up to 7 layers. Two lipid mono-layers in each membrane can stain as 3 layers plus one layer from the gap between them, similar to two stacked bread sandwiches with space between them

The term "gap junction" appeared to be coined about 16 years later circa 1969.^[77]^[78]^[79] A similar narrow regular gap was not demonstrated in other intercellular junctions photographed using the TEM at the time.

Form and indicator of function

Well before the demonstration of the "gap" in gap junctions they were seen at the junction of neighboring nerve cells. The close proximity of the neighboring cell membranes at the gap junction lead researchers to speculate that they had a role in intercellular communication, in particular the transmission of electrical signals.^[80]^[81]^[82] Gap junctions were also proven to be electrically rectifying and referred to as an electrical synapse.^[83]^[84] Later it was found that chemicals could also be transported between cells through gap junctions.^[85] Implicit or explicit in most of the early studies is that the area of the gap junction was different in structure to the surrounding membranes in a way that made it look different. The gap junction had been shown to create a micro-environment between the two cells in the extra-cellular space or "gap". This portion of extra-cellular space was somewhat isolated from the surrounding space and also bridged by what we now call connexon pairs which form even more tightly sealed bridges that cross the gap junction gap between two cells. When viewed in the plane of the membrane by freeze fracture techniques higher resolution distribution of connexons within the gap junction plaque is possible.^[86] Connexin free islands are observed in some junctions. The observation was largely without explanation until vesicles were shown by Peracchia using TEM thin sections to be systematically associated with gap junction plaques.^[87] Peracchia's study was probably also the first study to describe paired connexon structures which he called somewhat simply a "globule". Studies showing vesicles associated with gap junctions and proposing the vesicle contents may move across the junction plaques between two cells were rare as most studies focused on the connexons rather than vesicles. A later study using a combination of microscopy techniques confirmed the early evidence of a probable function for gap junctions in intercellular vesicle transfer. Areas of vesicle transfer were associated with connexin free islands within gap junction plaques.^[88]

Gap junctions and the electrical and chemical nerve synapses

Because of the widespread occurrence of gap junctions in cell types other than nerve cells the term gap junction became more generally used than terms such as electrical synapse or nexus. Another dimension in the relationship between nerve cells and gap junctions was revealed by studying chemical synapse formation and gap junction presence. By tracing nerve development in leeches with gap junction expression suppressed it was shown that the bidirectional gap junction (electrical nerve synapse) needs to form between two cells before they can grow to form a unidirectional "chemical nerve synapse".^[89] The chemical nerve synapse is the synapse most often truncated to the more ambiguous term "nerve synapse".

What is a gap junction made of?

Connexons

The purification^[90]^[91] of the intercellular gap junction plaques enriched in the channel forming protein (connexin) showed a protein forming hexagonal arrays in x-ray diffraction. Now systematic study and identification of the predominant gap junction protein^[92] became possible. Refined ultrastructural studies by TEM ^[93]^[94] showed protein occurred in a complementary fashion in both cells participating in a gap junction plaque. The gap junction plaque is a relatively large area of membrane observed in TEM thin section and freeze fracture (FF) seen filled with trans-membrane proteins in both tissues and more gently treated gap junction preparations. With the apparent ability for one protein alone to enable intercellular communication seen in gap junctions^[95] the term gap junction tended to became synonymous with a group of assembled connexins though this was not shown in vivo. Biochemical analysis of gap junction rich isolates from various tissues demonstrated a family of connexins.^[96]^[97]^[98]

Ultrastructure and biochemistry of isolated gap junctions already referenced had indicated the connexins preferentially group in gap junction plaques or domains and connexins were the best characterized constituent. It has been noted that the organisation of proteins into arrays with a gap junction plaque may be significant.^[19]^[99] It is likely this early work was already reflecting the presence of more than just connexins in gap junctions. Combining the emerging fields of freeze-fracture to see inside membranes and immunocytochemistry to label cell components (Freeze-fracture replica immunolabelling or FRIL and thin section immunolabelling) showed gap junction plaques in vivo contained the connexin protein.^[100]^[101] Later studies using immunofluorescence microscopy of larger areas of tissue clarified diversity in earlier results. Gap junction plaques were confirmed to have variable composition being home to connexon and non-connexin proteins as well making the modern usage of the terms "gap junction" and "gap junction plaque" non-interchangeable.^[102] In other words, the commonly used term "gap junction" always refers to a structure that contains connexins while a gap junction plaque may also contain other structural features that will define it.

The "plaque" or "formation plaque"

Early descriptions of "gap junctions" and "connexons" did not refer to them as such and many other terms were used. It is likely that "synaptic disks" ^[103] were an accurate reference to gap junction plaques. While the detailed structure and function of the connexon was described in a limited way at the time the gross "disk" structure was relatively large and easily seen by various TEM techniques. Disks allowed researchers using TEM to easily locate the connexons contained within the disk like patches in vivo and in vitro. The disk or "plaque" appeared to have structural properties different to those imparted by the connexons alone.^[104] It was thought that if the area of membrane in the plaque transmitted signals the area of membrane would have to be sealed in some way to prevent leakage.^[105] Later studies showed gap junction plaques are home to non-connexin proteins making the modern usage of the terms "gap junction" and "gap junction plaque" non-interchangeable as the area of the gap junction plaque may contain proteins other than connexins.^[102]^[106] Just as connexins do not always occupy the entire area of the plaque the other components described in the literature may be only long term or short term residents.^[107]

Studies allowing views inside the plane of the membrane of gap junctions during formation indicated that a "formation plaque" formed between two cells prior to the connexins moving in. They were particle free areas when observed by TEM FF indicating very small or no transmembrane proteins were likely present. Little is known about what structures make up the formation plaque or how the formation plaque's structure changes when connexins and other components move in or out. One of the earlier studies of the formation of small gap junctions describes rows of particles and particle free halos.^[108] With larger gap junctions they were described as formation plaques with connexins moving into them. The particulate gap junctions were thought to form 4–6 hours after the formation plaques appeared.^[109] How the connexins may be transported to the plaques using tubulin is becoming clearer.^[44]^[110]

Immunofluorescence microscopy video of connexins being moved along microtubles to the surface of a cell.^[111]

The formation plaque and non-connexin part of the classical gap junction plaque have been difficult for early researchers to analyse. It appears in TEM FF and thin section to be a lipid membrane domain that can somehow form a comparatively rigid barrier to other lipids and proteins. There has been indirect evidence for certain lipids being preferentially involved with the formation plaque but this cannot be considered definitive.^[112]^[113] It is difficult to envisage breaking up the membrane to analyse membrane plaques without affecting their composition. By study of connexins still in membranes lipids associated with the connexins have been studied.^[114] It was found that specific connexins tended to associate preferentially with specific phospholipids. As formation plaques precede connexins these results still give no certainty as to what is unique about the composition of plaques themselves. Other findings show connexins associate with protein scaffolds used in another junction, the zonula occludens ZO1.^[115] While this helps us understand how connexins may be moved into a gap junction formation plaque the composition of the plaque itself is still somewhat sketchy. Some headway on the in vivo composition of the gap junction plaque is being made using TEM FRIL.^[115]^[116]

References

^ White, Thomas W.; Paul, David L. (1999). "Genetic diseases and gene knockouts reveal diverse connexin functions". Annual review of physiology. 61: 283–310. doi:10.1146/annurev.physiol.61.1.283. PMID 10099690.
^ Kelsell, David P.; Dunlop, John; Hodgins, Malcolm B. (2001). "Human diseases: clues to cracking the connexin code?". Trends in cell biology. 11 (1): 2–6. doi:10.1016/S0962-8924(00)01866-3. PMID 11146276.
^ Willecke, Klaus; Eiberger, Jürgen; Degen, Joachim; Eckardt, Dominik; Romualdi, Alessandro; Güldenagel, Martin; Deutsch, Urban; Söhl, Goran (2002). "Structural and functional diversity of connexin genes in the mouse and human genome". Biological chemistry. 383 (5): 725–37. doi:10.1515/BC.2002.076. PMID 12108537.
^ ^a ^b Lampe, Paul D.; Lau, Alan F. (2004). "The effects of connexin phosphorylation on gap junctional communication". The international journal of biochemistry & cell biology. 36 (7): 1171–86. doi:10.1016/S1357-2725(03)00264-4. PMC 2878204. PMID 15109565.
^ ^a ^b Lampe, Paul D.; Lau, Alan F. (2000). "Regulation of gap junctions by phosphorylation of connexins". Archives of biochemistry and biophysics. 384 (2): 205–15. doi:10.1006/abbi.2000.2131. PMID 11368307.
^ ^a ^b Maeda, Shoji; Nakagawa, So; Suga, Michihiro; Yamashita, Eiki; Oshima, Atsunori; Fujiyoshi, Yoshinori; Tsukihara, Tomitake (2009). "Structure of the connexin 26 gap junction channel at 3.5 A resolution". Nature. 458 (7238): 597–602. doi:10.1038/nature07869. PMID 19340074.
^ ^a ^b Alberts, Bruce (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1.^{[page needed]}
^ Perkins, Guy A.; Goodenough, Daniel A.; Sosinsky, Gina E. (1998). "Formation of the gap junction intercellular channel requires a 30 degree rotation for interdigitating two apposing connexons". Journal of Molecular Biology. 277 (2): 171–7. doi:10.1006/jmbi.1997.1580. PMID 9514740.
^ Chang, Qing; Tang, Wenxue; Ahmad, Shoeb; Zhou, Binfei; Lin, Xi (2008). Schiffmann, Raphael (ed.). "Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice". PLoS ONE. 3 (12): e4088. doi:10.1371/journal.pone.0004088. PMC 2605248. PMID 19116647.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ Hu, X; Dahl, G (1999). "Exchange of conductance and gating properties between gap junction hemichannels". FEBS Lett. 451 (2): 113–117. doi:10.1016/S0014-5793(99)00558-X. PMID 10371149.
^ Loewenstein WR (1966) Permeability of membrane junctions. Ann N Y Acad Sci 137:441–472.
^ Robertson, JD (1953). "Ultrastructure of two invertebrate synapses". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 82 (2): 219–23. PMID 13037850. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Variations in tight and gap junctions in mammalian tissues.Friend DS, Gilula NB" J Cell Biol 1972 Jun;53(3) 758-76.
^ Hudspeth, AJ; Revel, JP. (1971). "Coexistence of gap and septate junctions in an invertebrate epithelium". J Cell Biol. 50 (1): 92–101. doi:10.1083/jcb.50.1.92. PMC 2108432. PMID 5563454. {{cite journal}}: Unknown parameter |month= ignored (help)
^ The structural organization of the septate and gap junctions of Hydra.Hand AR, Gobel S" J Cell Biol 1972 Feb;52(2) 397-408.
^ Raviola, E; Gilula, NB. (1973). "Gap junctions between photoreceptor cells in the vertebrate retina". Proc Natl Acad Sci U S A. 70 (6): 1677–81. Bibcode:1973PNAS...70.1677R. doi:10.1073/pnas.70.6.1677. PMC 433571. PMID 4198274. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Kreutziger GO. "Lateral membrane morphology and gap junction structure in rabbit corneal endothelium. Exp Eye Res. 1976 Sep;23(3) 285-93. PMC433571
^ J Cell Biol. 1971 March 1; 48(3) 455–472. PMCID: PMC2108114 DIFFERENTIATION OF THE JUNCTIONAL COMPLEX OF SURFACE CELLS IN THE DEVELOPING FUNDULUS BLASTODERM Thomas L. Lentz and J. P. Trinkaus
^ ^a ^b J Cell Biol. 1974 Jul;62(1) 32-47.Assembly of gap junctions during amphibian neurulation. Decker RS, Friend DS.
^ Albertini, DF; Anderson, E. (1974). "The appearance and structure of intercellular connections during the ontogeny of the rabbit ovarian follicle with particular reference to gap junctions". J Cell Biol. 63 (1): 234–50. doi:10.1083/jcb.63.1.234. PMC 2109337. PMID 4417791. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Proc Natl Acad Sci U S A. 1974 Nov;71(11) 4536-40. Gap junction formation between reaggregated Novikoff hepatoma cells. Johnson R, Hammer M, Sheridan J, Revel JP.
^ Knudsen, KA; Horwitz, AF. (1978). "Toward a mechanism of myoblast fusion". Prog Clin Biol Res. 23: 563–8. PMID 96453.
^ Tissue Cell. 1975;7(3) 575-85. Inverted gap and other cell junctions in cockroach hemocyte capsules: a thin section and freeze-fracture study. Baerwald RJ.
^ Cancer Res. 1975 Feb;35(2) 364-9. Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, Keratoacanthoma. Prutkin L.
^ Bellairs, R; Breathnach, AS; Gross, M. (1975). "Freeze-fracture replication of junctional complexes in unincubated and incubated chick embryos". Cell Tissue Res. 162 (2): 235–52. doi:10.1007/BF00209209. PMID 1237352. {{cite journal}}: Unknown parameter |month= ignored (help)
^ J Clin Endocrinol Metab. 1975 Nov;41(5) 841-4.Cell contacts in human islets of Langerhans. Orci L, Malaisse-Lagae F, Amherdt M, Ravazzola M, Weisswange A, Dobbs R, Perrelet A, Unger R.
^ J Neurocytol. 1977 Feb;6(1) 1-12. Gap junctions between the supporting cells in some acoustico-vestibular receptors. Hama K, Saito K.
^ Shibata, Y; Yamamoto, T (1977). "Gap junctions in the cardiac muscle cells of the lamprey". Cell Tissue Res. 178 (4): 477–82. PMID 870202. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Lorber, V; Rayns, DG (1977). "Fine structure of the gap junction in the tunicate heart". Cell Tissue Res. 179 (2): 169–75. PMID 858161. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Intercellular junctional complexes of the rat seminiferous tubules: a freeze-fracture study. McGinley D, Posalaky Z, Provaznik M. Anat Rec. 1977 Oct;189(2) 211-31.
^ Garfield, RE; Sims, SM; Kannan, MS; Daniel, EE (1978). "Possible role of gap junctions in activation of myometrium during parturition". Am. J. Physiol. 235 (5): C168–79. PMID 727239. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Goodenough, DA (1979). "Lens gap junctions: a structural hypothesis for nonregulated low-resistance intercellular pathways". Invest. Ophthalmol. Vis. Sci. 18 (11): 1104–22. PMID 511455. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Boucaud-Camou, Eve (1980). "Junctional structures in digestive epithelia of a cephalopod". Tissue Cell. 12 (2): 395–404. doi:10.1016/0040-8166(80)90013-0. PMID 7414602.
^ Anat Embryol (Berl). 1993 Apr;187(4) 343-52. The incidence and size of gap junctions between the bone cells in rat calvaria. Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, Green C
^ Sperelakis, Nicholas; Ramasamy, Lakshminarayanan (2005). "Gap-junction channels inhibit transverse propagation in cardiac muscle". Biomed Eng Online. 4 (1): 7. doi:10.1186/1475-925X-4-7. PMC 549032. PMID 15679888.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ J Membr Biol. 1977 Jun 3;34(1) 39-54.Intercellular communication and tissue growth: IX. Junctional membrane structure of hybrids between communication-competent and communication-incompetent cells.Larsen WJ, Azarnia R, Loewenstein WR.
^ Proc Natl Acad Sci U S A. 1977 Oct;74(10) 4476-80. Comparison of contact-mediated communication in normal and transformed human cells in culture.Corsaro CM, Migeon BR.
^ Habermann, H; Chang, WY; Birch, L; Mehta, P; Prins, GS (2001). "Developmental exposure to estrogens alters epithelial cell adhesion and gap junction proteins in the adult rat prostate". Endocrinology. 142 (1): 359–69. doi:10.1210/en.142.1.359. PMID 11145599. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Kelley, Robert O.; Vogel, Kathryn G.; Crissman, Harry A.; Lujan, Christopher J.; Skipper, Betty E. (1979). "Development of the aging cell surface. Reduction of gap junction-mediated metabolic cooperation with progressive subcultivation of human embryo fibroblasts (IMR-90)". Exp. Cell Res. 119 (1): 127–43. doi:10.1016/0014-4827(79)90342-2. PMID 761600. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Warner, Anne E.; Guthrie, Sarah C.; Gilula, Norton B. (1984). "Antibodies to gap-junctional protein selectively disrupt junctional communication in the early amphibian embryo". Nature. 311 (5982): 127–31. Bibcode:1984Natur.311..127W. doi:10.1038/311127a0. PMID 6088995.
^ Warner, AE (1987). "The use of antibodies to gap junction protein to explore the role of gap junctional communication during development". Ciba Found. Symp. 125: 154–67. PMID 3030673.
^ Bastide, B; Jarry-Guichard, T; Briand, JP; Délèze, J; Gros, D (1996). "Effect of antipeptide antibodies directed against three domains of connexin43 on the gap junctional permeability of cultured heart cells". J. Membr. Biol. 150 (3): 243–53. doi:10.1007/s002329900048. PMID 8661989. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Hofer, A; Dermietzel, R (1998). "Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes". Glia. 24 (1): 141–54. doi:10.1002/(SICI)1098-1136(199809)24:1<141::AID-GLIA13>3.0.CO;2-R. PMID 9700496. {{cite journal}}: Unknown parameter |month= ignored (help)
^ ^a ^b PLoS One. 2011;6(10) e26379. Epub 2011 Oct 14. Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics.Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C.
^ Levin, Michael; Mercola, Mark (1998). "Gap junctions are involved in the early generation of left-right asymmetry". Dev. Biol. 203 (1): 90–105. doi:10.1006/dbio.1998.9024. PMID 9806775. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Levin, M; Mercola, M (1999). "Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node". Development. 126 (21): 4703–14. PMID 10518488. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Bani-Yaghoub, Mahmud; Underhill, T. Michael; Naus, Christian C.G. (1999). "Gap junction blockage interferes with neuronal and astroglial differentiation of mouse P19 embryonal carcinoma cells". Dev. Genet. 24 (1–2): 69–81. doi:10.1002/(SICI)1520-6408(1999)24:1/2<69::AID-DVG8>3.0.CO;2-M. PMID 10079512.
^ Bani-Yaghoub, Mahmud; Bechberger, John F.; Underhill, T.Michael; Naus, Christian C.G. (1999). "The effects of gap junction blockage on neuronal differentiation of human NTera2/clone D1 cells". Exp. Neurol. 156 (1): 16–32. doi:10.1006/exnr.1998.6950. PMID 10192774. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Donahue, HJ; Li, Z; Zhou, Z; Yellowley, CE (2000). "Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication". Am. J. Physiol., Cell Physiol. 278 (2): C315–22. PMID 10666026. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Cronier, L.; Frendo, JL; Defamie, N; Pidoux, G; Bertin, G; Guibourdenche, J; Pointis, G; Malassine, A (2003). "Requirement of gap junctional intercellular communication for human villous trophoblast differentiation". Biol. Reprod. 69 (5): 1472–80. doi:10.1095/biolreprod.103.016360. PMID 12826585. {{cite journal}}: Unknown parameter |month= ignored (help)
^ El-Sabban, M. E.; Sfeir, AJ; Daher, MH; Kalaany, NY; Bassam, RA; Talhouk, RS (2003). "ECM-induced gap junctional communication enhances mammary epithelial cell differentiation". J. Cell. Sci. 116 (Pt 17): 3531–41. doi:10.1242/jcs.00656. PMID 12893812. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Chaytor, AT; Martin, PE; Evans, WH; Randall, MD; Griffith, TM (1999). "The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication". J. Physiol. (Lond.). 520 (2): 539–50. doi:10.1111/j.1469-7793.1999.00539.x. PMC 2269589. PMID 10523421. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Srinivas, M.; Hopperstad, MG; Spray, DC (2001). "Quinine blocks specific gap junction channel subtypes". Proc. Natl. Acad. Sci. U.S.A. 98 (19): 10942–7. doi:10.1073/pnas.191206198. PMC 58578. PMID 11535816. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Li Bi, Wan; Parysek, Linda M.; Warnick, Ronald; Stambrook, Peter J. (1993). "In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy". Hum. Gene Ther. 4 (6): 725–31. doi:10.1089/hum.1993.4.6-725. PMID 8186287. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Pitts, JD (1994). "Cancer gene therapy: a bystander effect using the gap junctional pathway". Mol. Carcinog. 11 (3): 127–30. doi:10.1002/mc.2940110302. PMID 7945800. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Colombo, Bruno M.; Benedetti, Sara; Ottolenghi, Sergio; Mora, Marina; Pollo, Bianca; Poli, Giorgio; Finocchiaro, Gaetano (1995). "The "bystander effect": association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice". Hum. Gene Ther. 6 (6): 763–72. doi:10.1089/hum.1995.6.6-763. PMID 7548276. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Fick, James; Barker, Fred G.; Dazin, Paul; Westphale, Eileen M.; Beyer, Eric C.; Israel, Mark A. (1995). "The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro". Proc. Natl. Acad. Sci. U.S.A. 92 (24): 11071–5. Bibcode:1995PNAS...9211071F. doi:10.1073/pnas.92.24.11071. PMC 40573. PMID 7479939. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Elshami, AA; Saavedra, A; Zhang, H; Kucharczuk, JC; Spray, DC; Fishman, GI; Amin, KM; Kaiser, LR; Albelda, SM (1996). "Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro". Gene Ther. 3 (1): 85–92. PMID 8929915. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Mesnil, Marc; Piccoli, Colette; Tiraby, Gerard; Willecke, Klaus; Yamasaki, Hiroshi (1996). "Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins". Proceedings of the National Academy of Sciences of the United States of America. 93 (5): 1831–5. Bibcode:1996PNAS...93.1831M. doi:10.1073/pnas.93.5.1831. PMC 39867. PMID 8700844. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Shinoura, Nobusada; Chen, Lin; Wani, Maqsood A.; Kim, Young Gyu; Larson, Jeffrey J.; Warnick, Ronald E.; Simon, Matthias; Menon, Anil G.; Bi, Wan Li (1996). "Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy". J. Neurosurg. 84 (5): 839–45, discussion 846. doi:10.3171/jns.1996.84.5.0839. PMID 8622159. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Hamel, W; Magnelli, L; Chiarugi, VP; Israel, MA (1996). "Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells". Cancer Res. 56 (12): 2697–702. PMID 8665496. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Sacco, MG; Benedetti, S; Duflot-Dancer, A; Mesnil, M; Bagnasco, L; Strina, D; Fasolo, V; Villa, A; MacChi, P (1996). "Partial regression, yet incomplete eradication of mammary tumors in transgenic mice by retrovirally mediated HSVtk transfer 'in vivo'". Gene Ther. 3 (12): 1151–6. PMID 8986442. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Ripps, Harris (2002). "Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect". Exp. Eye Res. 74 (3): 327–36. doi:10.1006/exer.2002.1155. PMID 12014914. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Little, JB; Azzam, EI; De Toledo, SM; Nagasawa, H (2002). "Bystander effects: intercellular transmission of radiation damage signals". Radiat Prot Dosimetry. 99 (1–4): 159–62. doi:10.1093/oxfordjournals.rpd.a006751. PMID 12194273.
^ Zhou, H; Randers-Pehrson, G; Suzuki, M; Waldren, CA; Hei, TK (2002). "Genotoxic damage in non-irradiated cells: contribution from the bystander effect". Radiat Prot Dosimetry. 99 (1–4): 227–32. doi:10.1093/oxfordjournals.rpd.a006769. PMID 12194291.
^ Lorimore, SA; Wright, EG (2003). "Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review". Int. J. Radiat. Biol. 79 (1): 15–25. PMID 12556327. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Ehrlich, HP; Diez, T (2003). "Role for gap junctional intercellular communications in wound repair". Wound Repair Regen. 11 (6): 481–9. doi:10.1046/j.1524-475X.2003.11616.x. PMID 14617290.
^ Coutinho, P.; Qiu, C.; Frank, S.; Wang, C.M.; Brown, T.; Green, C.R.; Becker, D.L. (2005). "Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury". Br J Plast Surg. 58 (5): 658–67. doi:10.1016/j.bjps.2004.12.022. PMID 15927148. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Wang, C. M.; Lincoln, J.; Cook, J. E.; Becker, D. L. (2007). "Abnormal connexin expression underlies delayed wound healing in diabetic skin". Diabetes. 56 (11): 2809–17. doi:10.2337/db07-0613. PMID 17717278. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Rivera, EM; Vargas, M; Ricks-Williamson, L (1997). "Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching". Pract Periodontics Aesthet Dent. 9 (1): 117–28. PMID 9550065.
^ Cusato, K; Bosco, A; Rozental, R; Guimarães, CA; Reese, BE; Linden, R; Spray, DC (2003). "Gap junctions mediate bystander cell death in developing retina". J. Neurosci. 23 (16): 6413–22. PMID 12878681. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Moyer, Kurtis E.; Saggers, Gregory C.; Ehrlich, H. Paul (2004). "Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication". Wound Repair Regen. 12 (3): 269–75. doi:10.1111/j.1067-1927.2004.012310.x. PMID 15225205.
^ Djalilian, A. R.; McGaughey, D; Patel, S; Seo, EY; Yang, C; Cheng, J; Tomic, M; Sinha, S; Ishida-Yamamoto, A (2006). "Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response". J. Clin. Invest. 116 (5): 1243–53. doi:10.1172/JCI27186. PMC 1440704. PMID 16628254. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Zhang, Y.; Wang, H.; Kovacs, A.; Kanter, E. M.; Yamada, K. A. (2010). "Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling". Am. J. Physiol. Heart Circ. Physiol. 298 (2): H477–87. doi:10.1152/ajpheart.00806.2009. PMC 2822575. PMID 19966054. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Orthmann-Murphy, Jennifer L. (May 2008). "Gap Junctions Couple Astrocytes and Oligodendrocytes". Journal of Molecular Neuroscience. 35 (1): 101–116. doi:10.1007/s12031-007-9027-5. PMC 2650399. PMID 18236012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
^ Revel, J. P.; Karnovsky, M. J.; Aitchison, EJ; Smith, EG; Farrell, ID; Gutschik, E (1967). "HEXAGONAL ARRAY OF SUBUNITS IN INTERCELLULAR JUNCTIONS OF THE MOUSE HEART AND LIVER". The Journal of Cell Biology. 33 (3): C7–C12. doi:10.1083/jcb.33.3.C7. PMC 2107199. PMID 2107199.
^ Brightman, MW; Reese, TS (1969). "Junctions between intimately apposed cell membranes in the vertebrate brain". J. Cell Biol. 40 (3): 648–77. doi:10.1083/jcb.40.3.648. PMC 2107650. PMID 5765759. {{cite journal}}: Unknown parameter |month= ignored (help)
^ DEMONSTRATION OF "GAP JUNCTIONS" BETWEEN SMOOTH MUSCLE CELLS Yasuo Uehara, Geoffrey Burnstock. J Cell Biol. 1970 January 1; 44(1) 215–217.PMCID: PMC2107775
^ Goodenough, DA; Revel, JP (1970). "A fine structural analysis of intercellular junctions in the mouse liver". J. Cell Biol. 45 (2): 272–90. doi:10.1083/jcb.45.2.272. PMC 2107902. PMID 4105112. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Robertson, J. D. (1953). "Ultrastructure of two invertebrate synapses". Proceedings of the Society for Experimental Biology and Medicine. 82 (2): 219–23. PMID 13037850.
^ Robertson, J. D. (1963). Locke, Michael (ed.). Cellular membranes in development. New York: Academic Press. OCLC 261587041.^{[page needed]}
^ Robertson (1981). "Membrane structure". The Journal of Cell Biology. 91 (3): 189s–204s. doi:10.1083/jcb.91.3.189s. JSTOR 1609517. PMC 2112820. PMID 7033238.
^ Furshpan, E. J.; Potter, D. D. (1957). "Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse". Nature. 180 (4581): 342–3. doi:10.1038/180342a0. PMID 13464833.
^ Furshpan; Potter, DD (1959). "Transmission at the giant motor synapses of the crayfish". The Journal of physiology. 145 (2): 289–325. PMC 1356828. PMID 13642302.
^ Payton, B. W.; Bennett, M. V. L.; Pappas, G. D. (1969). "Permeability and structure of junctional membranes at an electrotonic synapse". Science. 166 (3913): 1641–3. doi:10.1126/science.166.3913.1641. PMID 5360587. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Chalcroft, J. P.; Bullivant, S (1970). "An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture". J. Cell Biol. 47 (1): 49–60. doi:10.1083/jcb.47.1.49. PMC 2108397. PMID 4935338. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Peracchia, C (1973). "Low resistance junctions in crayfish. II. Structural details and further evidence for intercellular channels by freeze-fracture and negative staining". J. Cell Biol. 57 (1): 54–65. PMC 2108965. PMID 4120610. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Gruijters, W (2003). "Are gap junction membrane plaques implicated in intercellular vesicle transfer?". Cell Biol. Int. 27 (9): 711–7. doi:10.1016/S1065-6995(03)00140-9. PMID 12972275.
^ J Neurosci. 2010 Nov 10;30(45) 15277-85. Gap junction expression is required for normal chemical synapse formation. Todd KL, Kristan WB Jr, French KA.
^ Goodenough, D. A.; Stoeckenius, W (1972). "THE ISOLATION OF MOUSE HEPATOCYTE GAP JUNCTIONS : Preliminary Chemical Characterization and X-Ray Diffraction". The Journal of Cell Biology. 54 (3): 646–56. doi:10.1083/jcb.54.3.646. PMC 2200277. PMID 4339819.
^ Goodenough, D. A. (1974). "BULK ISOLATION OF MOUSE HEPATOCYTE GAP JUNCTIONS : Characterization of the Principal Protein, Connexin". The Journal of Cell Biology. 61 (2): 557–63. doi:10.1083/jcb.61.2.557. PMC 2109294. PMID 4363961.
^ Kumar, N. M.; Gilula, NB (1986). "Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein". The Journal of Cell Biology. 103 (3): 767–76. doi:10.1083/jcb.103.3.767. PMC 2114303. PMID 2875078.
^ J Cell Biol. 1970 Dec;47(3) 666-88.The ultrastructure of the nexus. A correlated thin-section and freeze-cleave study. McNutt NS, Weinstein RS.
^ Chalcroft, J. P.; Bullivant, S (1970). "AN INTERPRETATION OF LIVER CELL MEMBRANE AND JUNCTION STRUCTURE BASED ON OBSERVATION OF FREEZE-FRACTURE REPLICAS OF BOTH SIDES OF THE FRACTURE". The Journal of Cell Biology. 47 (1): 49–60. doi:10.1083/jcb.47.1.49. PMC 2108397. PMID 4935338.
^ Young; Cohn, ZA; Gilula, NB (1987). "Functional assembly of gap junction conductance in lipid bilayers: demonstration that the major 27 kd protein forms the junctional channel". Cell. 48 (5): 733–43. doi:10.1016/0092-8674(87)90071-7. PMID 3815522.
^ Nicholson; Gros, DB; Kent, SB; Hood, LE; Revel, JP (1985). "The Mr 28,000 gap junction proteins from rat heart and liver are different but related". The Journal of Biological Chemistry. 260 (11): 6514–7. PMID 2987225.
^ Beyer, E. C.; Paul, DL; Goodenough, DA (1987). "Connexin43: a protein from rat heart homologous to a gap junction protein from liver". The Journal of Cell Biology. 105 (6 Pt 1): 2621–9. doi:10.1083/jcb.105.6.2621. PMC 2114703. PMID 2826492.
^ Kistler, J; Kirkland, B; Bullivant, S (1985). "Identification of a 70,000-D protein in lens membrane junctional domains". The Journal of Cell Biology. 101 (1): 28–35. doi:10.1083/jcb.101.1.28. PMC 2113615. PMID 3891760.
^ Three types of gap junctions interconnecting intestinal epithelial cells visualized by freeze-etching. Staehelin LA" Proc Natl Acad Sci U S A 1972 May;69(5) 1318-21.
^ Gruijters, WTM; Kistler, J; Bullivant, S; Goodenough, DA (1987). "Immunolocalization of MP70 in lens fiber 16-17-nm intercellular junctions". The Journal of Cell Biology. 104 (3): 565–72. doi:10.1083/jcb.104.3.565. PMC 2114558. PMID 3818793.
^ Gruijters, WTM; Kistler, J; Bullivant, S (1987). "Formation, distribution and dissociation of intercellular junctions in the lens". Journal of Cell Science. 88 (3): 351–9. PMID 3448099.
^ ^a ^b Gruijters, WTM (1989). "A non-connexon protein (MIP) is involved in eye lens gap-junction formation". Journal of Cell Science. 93 (3): 509–13. PMID 2691517.
^ Robertson, JD (1963). "THE OCCURRENCE OF A SUBUNIT PATTERN IN THE UNIT MEMBRANES OF CLUB ENDINGS IN MAUTHNER CELL SYNAPSES IN GOLDFISH BRAINS". J. Cell Biol. 19 (1): 201–21. doi:10.1083/jcb.19.1.201. PMC 2106854. PMID 14069795. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Hand, AR; Gobel, S (1972). "The structural organization of the septate and gap junctions of Hydra". J. Cell Biol. 52 (2): 397–408. doi:10.1083/jcb.52.2.397. PMC 2108629. PMID 4109925. {{cite journal}}: Unknown parameter |month= ignored (help)
^ STUDIES ON AN EPITHELIAL (GLAND) CELL JUNCTION : I. Modifications of Surface Membrane Permeability Werner R. Loewenstein, Yoshinobu Kanno J Cell Biol. 1964 September 1; 22(3) 565–586. PMCID
^ Gruijters, WTM (2003). "Are gap junction membrane plaques implicated in intercellular vesicle transfer?". Cell Biology International. 27 (9): 711–7. doi:10.1016/S1065-6995(03)00140-9. PMID 12972275.
^ Ozato-Sakurai N, Fujita A, Fujimoto T. "The distribution of phosphatidylinositol 4,5-bisphosphate in acinar cells of rat pancreas revealed with the freeze-fracture replica labeling method. PLoS One. 2011;6(8) e23567. Epub 2011 Aug 15.
^ Decker, RS; Friend, DS (1974). "Assembly of gap junctions during amphibian neurulation". J. Cell Biol. 62 (1): 32–47. doi:10.1083/jcb.62.1.32. PMC 2109180. PMID 4135001. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Decker, RS (1976). "Hormonal regulation of gap junction differentiation". J. Cell Biol. 69 (3): 669–85. doi:10.1083/jcb.69.3.669. PMC 2109697. PMID 1083855. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Proc Natl Acad Sci U S A. 2002 Aug 6;99(16) 10446-51. Epub 2002 Jul 29. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM.
^ PLoS One. 2011;6(10) e26379. Epub 2011 Oct 14. Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics. Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C. Source Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
^ Meyer, R; Malewicz, B; Baumann, WJ; Johnson, RG (1990). "Increased gap junction assembly between cultured cells upon cholesterol supplementation". J. Cell. Sci. 96 (2): 231–8. PMID 1698798. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Johnson, R. G.; Reynhout, J. K.; Tenbroek, E. M.; Quade, B. J.; Yasumura, T.; Davidson, K. G. V.; Sheridan, J. D.; Rash, J. E. (2012). "Gap junction assembly: roles for the formation plaque and regulation by the C-terminus of connexin43". Mol. Biol. Cell. 23 (1): 71–86. doi:10.1091/mbc.E11-02-0141. PMC 3248906. PMID 22049024. {{cite journal}}: Unknown parameter |month= ignored (help)
^ Locke, Darren; Harris, Andrew L (2009). "Connexin channels and phospholipids: association and modulation". BMC Biol. 7: 52. doi:10.1186/1741-7007-7-52. PMC 2733891. PMID 19686581.{{cite journal}}: CS1 maint: unflagged free DOI (link)
^ ^a ^b Connexin45-containing neuronal gap junctions in rodent retina also contain connexin36 in both apposing hemiplaques, forming bi-homotypic gap junctions, with scaffolding contributed by zonula occludens-1 Xinbo Li, Naomi Kamasawa, Cristina Ciolofan, Carl O. Olson, Shijun Lu, Kimberly G.V. Davidson, Thomas Yasumura, Ryuichi Shigemoto, John E. Rash, James I. Nagy J Neurosci. Author manuscript; available in PMC 2009 March 24.Published in final edited form as: J Neurosci. 2008 September 24; 28(39) 9769–9789. doi: 10.1523/JNEUROSCI.2137-08.2008 PMCID: PMC2638127
^ The Distribution of Phosphatidylinositol 4,5-Bisphosphate in Acinar Cells of Rat Pancreas Revealed with the Freeze-Fracture Replica Labeling Method Nami Ozato-Sakurai, Akikazu Fujita, Toyoshi Fujimoto PLoS One. 2011; 6(8) e23567. Published online 2011 August 15. doi: 10.1371/journal.pone.0023567 PMCID: PMC3156236

External links

Gap+Junctions at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

[1] White, Thomas W.; Paul, David L. (1999). "Genetic diseases and gene knockouts reveal diverse connexin functions". Annual review of physiology. 61: 283–310. doi:10.1146/annurev.physiol.61.1.283. PMID 10099690.

[2] Kelsell, David P.; Dunlop, John; Hodgins, Malcolm B. (2001). "Human diseases: clues to cracking the connexin code?". Trends in cell biology. 11 (1): 2–6. doi:10.1016/S0962-8924(00)01866-3. PMID 11146276.

[3] Willecke, Klaus; Eiberger, Jürgen; Degen, Joachim; Eckardt, Dominik; Romualdi, Alessandro; Güldenagel, Martin; Deutsch, Urban; Söhl, Goran (2002). "Structural and functional diversity of connexin genes in the mouse and human genome". Biological chemistry. 383 (5): 725–37. doi:10.1515/BC.2002.076. PMID 12108537.

[gj1-4] Lampe, Paul D.; Lau, Alan F. (2004). "The effects of connexin phosphorylation on gap junctional communication". The international journal of biochemistry & cell biology. 36 (7): 1171–86. doi:10.1016/S1357-2725(03)00264-4. PMC 2878204. PMID 15109565.

[gj2-5] Lampe, Paul D.; Lau, Alan F. (2000). "Regulation of gap junctions by phosphorylation of connexins". Archives of biochemistry and biophysics. 384 (2): 205–15. doi:10.1006/abbi.2000.2131. PMID 11368307.

[maeda-6] Maeda, Shoji; Nakagawa, So; Suga, Michihiro; Yamashita, Eiki; Oshima, Atsunori; Fujiyoshi, Yoshinori; Tsukihara, Tomitake (2009). "Structure of the connexin 26 gap junction channel at 3.5 A resolution". Nature. 458 (7238): 597–602. doi:10.1038/nature07869. PMID 19340074.

[mbc-7] Alberts, Bruce (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1.^{[page needed]}

[8] Perkins, Guy A.; Goodenough, Daniel A.; Sosinsky, Gina E. (1998). "Formation of the gap junction intercellular channel requires a 30 degree rotation for interdigitating two apposing connexons". Journal of Molecular Biology. 277 (2): 171–7. doi:10.1006/jmbi.1997.1580. PMID 9514740.

[9] Chang, Qing; Tang, Wenxue; Ahmad, Shoeb; Zhou, Binfei; Lin, Xi (2008). Schiffmann, Raphael (ed.). "Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice". PLoS ONE. 3 (12): e4088. doi:10.1371/journal.pone.0004088. PMC 2605248. PMID 19116647.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[10] Hu, X; Dahl, G (1999). "Exchange of conductance and gating properties between gap junction hemichannels". FEBS Lett. 451 (2): 113–117. doi:10.1016/S0014-5793(99)00558-X. PMID 10371149.

[11] Loewenstein WR (1966) Permeability of membrane junctions. Ann N Y Acad Sci 137:441–472.

[12] Robertson, JD (1953). "Ultrastructure of two invertebrate synapses". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine. 82 (2): 219–23. PMID 13037850. {{cite journal}}: Unknown parameter |month= ignored (help)

[13] Variations in tight and gap junctions in mammalian tissues.Friend DS, Gilula NB" J Cell Biol 1972 Jun;53(3) 758-76.

[14] Hudspeth, AJ; Revel, JP. (1971). "Coexistence of gap and septate junctions in an invertebrate epithelium". J Cell Biol. 50 (1): 92–101. doi:10.1083/jcb.50.1.92. PMC 2108432. PMID 5563454. {{cite journal}}: Unknown parameter |month= ignored (help)

[15] The structural organization of the septate and gap junctions of Hydra.Hand AR, Gobel S" J Cell Biol 1972 Feb;52(2) 397-408.

[16] Raviola, E; Gilula, NB. (1973). "Gap junctions between photoreceptor cells in the vertebrate retina". Proc Natl Acad Sci U S A. 70 (6): 1677–81. Bibcode:1973PNAS...70.1677R. doi:10.1073/pnas.70.6.1677. PMC 433571. PMID 4198274. {{cite journal}}: Unknown parameter |month= ignored (help)

[17] Kreutziger GO. "Lateral membrane morphology and gap junction structure in rabbit corneal endothelium. Exp Eye Res. 1976 Sep;23(3) 285-93. PMC433571

[18] J Cell Biol. 1971 March 1; 48(3) 455–472. PMCID: PMC2108114 DIFFERENTIATION OF THE JUNCTIONAL COMPLEX OF SURFACE CELLS IN THE DEVELOPING FUNDULUS BLASTODERM Thomas L. Lentz and J. P. Trinkaus

[ReferenceA-19] J Cell Biol. 1974 Jul;62(1) 32-47.Assembly of gap junctions during amphibian neurulation. Decker RS, Friend DS.

[20] Albertini, DF; Anderson, E. (1974). "The appearance and structure of intercellular connections during the ontogeny of the rabbit ovarian follicle with particular reference to gap junctions". J Cell Biol. 63 (1): 234–50. doi:10.1083/jcb.63.1.234. PMC 2109337. PMID 4417791. {{cite journal}}: Unknown parameter |month= ignored (help)

[21] Proc Natl Acad Sci U S A. 1974 Nov;71(11) 4536-40. Gap junction formation between reaggregated Novikoff hepatoma cells. Johnson R, Hammer M, Sheridan J, Revel JP.

[22] Knudsen, KA; Horwitz, AF. (1978). "Toward a mechanism of myoblast fusion". Prog Clin Biol Res. 23: 563–8. PMID 96453.

[23] Tissue Cell. 1975;7(3) 575-85. Inverted gap and other cell junctions in cockroach hemocyte capsules: a thin section and freeze-fracture study. Baerwald RJ.

[24] Cancer Res. 1975 Feb;35(2) 364-9. Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, Keratoacanthoma. Prutkin L.

[25] Bellairs, R; Breathnach, AS; Gross, M. (1975). "Freeze-fracture replication of junctional complexes in unincubated and incubated chick embryos". Cell Tissue Res. 162 (2): 235–52. doi:10.1007/BF00209209. PMID 1237352. {{cite journal}}: Unknown parameter |month= ignored (help)

[26] J Clin Endocrinol Metab. 1975 Nov;41(5) 841-4.Cell contacts in human islets of Langerhans. Orci L, Malaisse-Lagae F, Amherdt M, Ravazzola M, Weisswange A, Dobbs R, Perrelet A, Unger R.

[27] J Neurocytol. 1977 Feb;6(1) 1-12. Gap junctions between the supporting cells in some acoustico-vestibular receptors. Hama K, Saito K.

[28] Shibata, Y; Yamamoto, T (1977). "Gap junctions in the cardiac muscle cells of the lamprey". Cell Tissue Res. 178 (4): 477–82. PMID 870202. {{cite journal}}: Unknown parameter |month= ignored (help)

[29] Lorber, V; Rayns, DG (1977). "Fine structure of the gap junction in the tunicate heart". Cell Tissue Res. 179 (2): 169–75. PMID 858161. {{cite journal}}: Unknown parameter |month= ignored (help)

[30] Intercellular junctional complexes of the rat seminiferous tubules: a freeze-fracture study. McGinley D, Posalaky Z, Provaznik M. Anat Rec. 1977 Oct;189(2) 211-31.

[31] Garfield, RE; Sims, SM; Kannan, MS; Daniel, EE (1978). "Possible role of gap junctions in activation of myometrium during parturition". Am. J. Physiol. 235 (5): C168–79. PMID 727239. {{cite journal}}: Unknown parameter |month= ignored (help)

[32] Goodenough, DA (1979). "Lens gap junctions: a structural hypothesis for nonregulated low-resistance intercellular pathways". Invest. Ophthalmol. Vis. Sci. 18 (11): 1104–22. PMID 511455. {{cite journal}}: Unknown parameter |month= ignored (help)

[33] Boucaud-Camou, Eve (1980). "Junctional structures in digestive epithelia of a cephalopod". Tissue Cell. 12 (2): 395–404. doi:10.1016/0040-8166(80)90013-0. PMID 7414602.

[34] Anat Embryol (Berl). 1993 Apr;187(4) 343-52. The incidence and size of gap junctions between the bone cells in rat calvaria. Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, Green C

[35] Sperelakis, Nicholas; Ramasamy, Lakshminarayanan (2005). "Gap-junction channels inhibit transverse propagation in cardiac muscle". Biomed Eng Online. 4 (1): 7. doi:10.1186/1475-925X-4-7. PMC 549032. PMID 15679888.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[36] J Membr Biol. 1977 Jun 3;34(1) 39-54.Intercellular communication and tissue growth: IX. Junctional membrane structure of hybrids between communication-competent and communication-incompetent cells.Larsen WJ, Azarnia R, Loewenstein WR.

[37] Proc Natl Acad Sci U S A. 1977 Oct;74(10) 4476-80. Comparison of contact-mediated communication in normal and transformed human cells in culture.Corsaro CM, Migeon BR.

[38] Habermann, H; Chang, WY; Birch, L; Mehta, P; Prins, GS (2001). "Developmental exposure to estrogens alters epithelial cell adhesion and gap junction proteins in the adult rat prostate". Endocrinology. 142 (1): 359–69. doi:10.1210/en.142.1.359. PMID 11145599. {{cite journal}}: Unknown parameter |month= ignored (help)

[39] Kelley, Robert O.; Vogel, Kathryn G.; Crissman, Harry A.; Lujan, Christopher J.; Skipper, Betty E. (1979). "Development of the aging cell surface. Reduction of gap junction-mediated metabolic cooperation with progressive subcultivation of human embryo fibroblasts (IMR-90)". Exp. Cell Res. 119 (1): 127–43. doi:10.1016/0014-4827(79)90342-2. PMID 761600. {{cite journal}}: Unknown parameter |month= ignored (help)

[40] Warner, Anne E.; Guthrie, Sarah C.; Gilula, Norton B. (1984). "Antibodies to gap-junctional protein selectively disrupt junctional communication in the early amphibian embryo". Nature. 311 (5982): 127–31. Bibcode:1984Natur.311..127W. doi:10.1038/311127a0. PMID 6088995.

[41] Warner, AE (1987). "The use of antibodies to gap junction protein to explore the role of gap junctional communication during development". Ciba Found. Symp. 125: 154–67. PMID 3030673.

[42] Bastide, B; Jarry-Guichard, T; Briand, JP; Délèze, J; Gros, D (1996). "Effect of antipeptide antibodies directed against three domains of connexin43 on the gap junctional permeability of cultured heart cells". J. Membr. Biol. 150 (3): 243–53. doi:10.1007/s002329900048. PMID 8661989. {{cite journal}}: Unknown parameter |month= ignored (help)

[43] Hofer, A; Dermietzel, R (1998). "Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes". Glia. 24 (1): 141–54. doi:10.1002/(SICI)1098-1136(199809)24:1<141::AID-GLIA13>3.0.CO;2-R. PMID 9700496. {{cite journal}}: Unknown parameter |month= ignored (help)

[ReferenceB-44] PLoS One. 2011;6(10) e26379. Epub 2011 Oct 14. Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics.Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C.

[45] Levin, Michael; Mercola, Mark (1998). "Gap junctions are involved in the early generation of left-right asymmetry". Dev. Biol. 203 (1): 90–105. doi:10.1006/dbio.1998.9024. PMID 9806775. {{cite journal}}: Unknown parameter |month= ignored (help)

[46] Levin, M; Mercola, M (1999). "Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node". Development. 126 (21): 4703–14. PMID 10518488. {{cite journal}}: Unknown parameter |month= ignored (help)

[47] Bani-Yaghoub, Mahmud; Underhill, T. Michael; Naus, Christian C.G. (1999). "Gap junction blockage interferes with neuronal and astroglial differentiation of mouse P19 embryonal carcinoma cells". Dev. Genet. 24 (1–2): 69–81. doi:10.1002/(SICI)1520-6408(1999)24:1/2<69::AID-DVG8>3.0.CO;2-M. PMID 10079512.

[48] Bani-Yaghoub, Mahmud; Bechberger, John F.; Underhill, T.Michael; Naus, Christian C.G. (1999). "The effects of gap junction blockage on neuronal differentiation of human NTera2/clone D1 cells". Exp. Neurol. 156 (1): 16–32. doi:10.1006/exnr.1998.6950. PMID 10192774. {{cite journal}}: Unknown parameter |month= ignored (help)

[49] Donahue, HJ; Li, Z; Zhou, Z; Yellowley, CE (2000). "Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication". Am. J. Physiol., Cell Physiol. 278 (2): C315–22. PMID 10666026. {{cite journal}}: Unknown parameter |month= ignored (help)

[50] Cronier, L.; Frendo, JL; Defamie, N; Pidoux, G; Bertin, G; Guibourdenche, J; Pointis, G; Malassine, A (2003). "Requirement of gap junctional intercellular communication for human villous trophoblast differentiation". Biol. Reprod. 69 (5): 1472–80. doi:10.1095/biolreprod.103.016360. PMID 12826585. {{cite journal}}: Unknown parameter |month= ignored (help)

[51] El-Sabban, M. E.; Sfeir, AJ; Daher, MH; Kalaany, NY; Bassam, RA; Talhouk, RS (2003). "ECM-induced gap junctional communication enhances mammary epithelial cell differentiation". J. Cell. Sci. 116 (Pt 17): 3531–41. doi:10.1242/jcs.00656. PMID 12893812. {{cite journal}}: Unknown parameter |month= ignored (help)

[52] Chaytor, AT; Martin, PE; Evans, WH; Randall, MD; Griffith, TM (1999). "The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication". J. Physiol. (Lond.). 520 (2): 539–50. doi:10.1111/j.1469-7793.1999.00539.x. PMC 2269589. PMID 10523421. {{cite journal}}: Unknown parameter |month= ignored (help)

[53] Srinivas, M.; Hopperstad, MG; Spray, DC (2001). "Quinine blocks specific gap junction channel subtypes". Proc. Natl. Acad. Sci. U.S.A. 98 (19): 10942–7. doi:10.1073/pnas.191206198. PMC 58578. PMID 11535816. {{cite journal}}: Unknown parameter |month= ignored (help)

[54] Li Bi, Wan; Parysek, Linda M.; Warnick, Ronald; Stambrook, Peter J. (1993). "In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy". Hum. Gene Ther. 4 (6): 725–31. doi:10.1089/hum.1993.4.6-725. PMID 8186287. {{cite journal}}: Unknown parameter |month= ignored (help)

[55] Pitts, JD (1994). "Cancer gene therapy: a bystander effect using the gap junctional pathway". Mol. Carcinog. 11 (3): 127–30. doi:10.1002/mc.2940110302. PMID 7945800. {{cite journal}}: Unknown parameter |month= ignored (help)

[56] Colombo, Bruno M.; Benedetti, Sara; Ottolenghi, Sergio; Mora, Marina; Pollo, Bianca; Poli, Giorgio; Finocchiaro, Gaetano (1995). "The "bystander effect": association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice". Hum. Gene Ther. 6 (6): 763–72. doi:10.1089/hum.1995.6.6-763. PMID 7548276. {{cite journal}}: Unknown parameter |month= ignored (help)

[57] Fick, James; Barker, Fred G.; Dazin, Paul; Westphale, Eileen M.; Beyer, Eric C.; Israel, Mark A. (1995). "The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro". Proc. Natl. Acad. Sci. U.S.A. 92 (24): 11071–5. Bibcode:1995PNAS...9211071F. doi:10.1073/pnas.92.24.11071. PMC 40573. PMID 7479939. {{cite journal}}: Unknown parameter |month= ignored (help)

[58] Elshami, AA; Saavedra, A; Zhang, H; Kucharczuk, JC; Spray, DC; Fishman, GI; Amin, KM; Kaiser, LR; Albelda, SM (1996). "Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro". Gene Ther. 3 (1): 85–92. PMID 8929915. {{cite journal}}: Unknown parameter |month= ignored (help)

[59] Mesnil, Marc; Piccoli, Colette; Tiraby, Gerard; Willecke, Klaus; Yamasaki, Hiroshi (1996). "Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins". Proceedings of the National Academy of Sciences of the United States of America. 93 (5): 1831–5. Bibcode:1996PNAS...93.1831M. doi:10.1073/pnas.93.5.1831. PMC 39867. PMID 8700844. {{cite journal}}: Unknown parameter |month= ignored (help)

[60] Shinoura, Nobusada; Chen, Lin; Wani, Maqsood A.; Kim, Young Gyu; Larson, Jeffrey J.; Warnick, Ronald E.; Simon, Matthias; Menon, Anil G.; Bi, Wan Li (1996). "Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy". J. Neurosurg. 84 (5): 839–45, discussion 846. doi:10.3171/jns.1996.84.5.0839. PMID 8622159. {{cite journal}}: Unknown parameter |month= ignored (help)

[61] Hamel, W; Magnelli, L; Chiarugi, VP; Israel, MA (1996). "Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells". Cancer Res. 56 (12): 2697–702. PMID 8665496. {{cite journal}}: Unknown parameter |month= ignored (help)

[62] Sacco, MG; Benedetti, S; Duflot-Dancer, A; Mesnil, M; Bagnasco, L; Strina, D; Fasolo, V; Villa, A; MacChi, P (1996). "Partial regression, yet incomplete eradication of mammary tumors in transgenic mice by retrovirally mediated HSVtk transfer 'in vivo'". Gene Ther. 3 (12): 1151–6. PMID 8986442. {{cite journal}}: Unknown parameter |month= ignored (help)

[63] Ripps, Harris (2002). "Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect". Exp. Eye Res. 74 (3): 327–36. doi:10.1006/exer.2002.1155. PMID 12014914. {{cite journal}}: Unknown parameter |month= ignored (help)

[64] Little, JB; Azzam, EI; De Toledo, SM; Nagasawa, H (2002). "Bystander effects: intercellular transmission of radiation damage signals". Radiat Prot Dosimetry. 99 (1–4): 159–62. doi:10.1093/oxfordjournals.rpd.a006751. PMID 12194273.

[65] Zhou, H; Randers-Pehrson, G; Suzuki, M; Waldren, CA; Hei, TK (2002). "Genotoxic damage in non-irradiated cells: contribution from the bystander effect". Radiat Prot Dosimetry. 99 (1–4): 227–32. doi:10.1093/oxfordjournals.rpd.a006769. PMID 12194291.

[66] Lorimore, SA; Wright, EG (2003). "Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review". Int. J. Radiat. Biol. 79 (1): 15–25. PMID 12556327. {{cite journal}}: Unknown parameter |month= ignored (help)

[67] Ehrlich, HP; Diez, T (2003). "Role for gap junctional intercellular communications in wound repair". Wound Repair Regen. 11 (6): 481–9. doi:10.1046/j.1524-475X.2003.11616.x. PMID 14617290.

[68] Coutinho, P.; Qiu, C.; Frank, S.; Wang, C.M.; Brown, T.; Green, C.R.; Becker, D.L. (2005). "Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury". Br J Plast Surg. 58 (5): 658–67. doi:10.1016/j.bjps.2004.12.022. PMID 15927148. {{cite journal}}: Unknown parameter |month= ignored (help)

[69] Wang, C. M.; Lincoln, J.; Cook, J. E.; Becker, D. L. (2007). "Abnormal connexin expression underlies delayed wound healing in diabetic skin". Diabetes. 56 (11): 2809–17. doi:10.2337/db07-0613. PMID 17717278. {{cite journal}}: Unknown parameter |month= ignored (help)

[70] Rivera, EM; Vargas, M; Ricks-Williamson, L (1997). "Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching". Pract Periodontics Aesthet Dent. 9 (1): 117–28. PMID 9550065.

[71] Cusato, K; Bosco, A; Rozental, R; Guimarães, CA; Reese, BE; Linden, R; Spray, DC (2003). "Gap junctions mediate bystander cell death in developing retina". J. Neurosci. 23 (16): 6413–22. PMID 12878681. {{cite journal}}: Unknown parameter |month= ignored (help)

[72] Moyer, Kurtis E.; Saggers, Gregory C.; Ehrlich, H. Paul (2004). "Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication". Wound Repair Regen. 12 (3): 269–75. doi:10.1111/j.1067-1927.2004.012310.x. PMID 15225205.

[73] Djalilian, A. R.; McGaughey, D; Patel, S; Seo, EY; Yang, C; Cheng, J; Tomic, M; Sinha, S; Ishida-Yamamoto, A (2006). "Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response". J. Clin. Invest. 116 (5): 1243–53. doi:10.1172/JCI27186. PMC 1440704. PMID 16628254. {{cite journal}}: Unknown parameter |month= ignored (help)

[74] Zhang, Y.; Wang, H.; Kovacs, A.; Kanter, E. M.; Yamada, K. A. (2010). "Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling". Am. J. Physiol. Heart Circ. Physiol. 298 (2): H477–87. doi:10.1152/ajpheart.00806.2009. PMC 2822575. PMID 19966054. {{cite journal}}: Unknown parameter |month= ignored (help)

[75] Orthmann-Murphy, Jennifer L. (May 2008). "Gap Junctions Couple Astrocytes and Oligodendrocytes". Journal of Molecular Neuroscience. 35 (1): 101–116. doi:10.1007/s12031-007-9027-5. PMC 2650399. PMID 18236012. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)

[76] Revel, J. P.; Karnovsky, M. J.; Aitchison, EJ; Smith, EG; Farrell, ID; Gutschik, E (1967). "HEXAGONAL ARRAY OF SUBUNITS IN INTERCELLULAR JUNCTIONS OF THE MOUSE HEART AND LIVER". The Journal of Cell Biology. 33 (3): C7–C12. doi:10.1083/jcb.33.3.C7. PMC 2107199. PMID 2107199.

[77] Brightman, MW; Reese, TS (1969). "Junctions between intimately apposed cell membranes in the vertebrate brain". J. Cell Biol. 40 (3): 648–77. doi:10.1083/jcb.40.3.648. PMC 2107650. PMID 5765759. {{cite journal}}: Unknown parameter |month= ignored (help)

[78] DEMONSTRATION OF "GAP JUNCTIONS" BETWEEN SMOOTH MUSCLE CELLS Yasuo Uehara, Geoffrey Burnstock. J Cell Biol. 1970 January 1; 44(1) 215–217.PMCID: PMC2107775

[79] Goodenough, DA; Revel, JP (1970). "A fine structural analysis of intercellular junctions in the mouse liver". J. Cell Biol. 45 (2): 272–90. doi:10.1083/jcb.45.2.272. PMC 2107902. PMID 4105112. {{cite journal}}: Unknown parameter |month= ignored (help)

[80] Robertson, J. D. (1953). "Ultrastructure of two invertebrate synapses". Proceedings of the Society for Experimental Biology and Medicine. 82 (2): 219–23. PMID 13037850.

[81] Robertson, J. D. (1963). Locke, Michael (ed.). Cellular membranes in development. New York: Academic Press. OCLC 261587041.^{[page needed]}

[82] Robertson (1981). "Membrane structure". The Journal of Cell Biology. 91 (3): 189s–204s. doi:10.1083/jcb.91.3.189s. JSTOR 1609517. PMC 2112820. PMID 7033238.

[83] Furshpan, E. J.; Potter, D. D. (1957). "Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse". Nature. 180 (4581): 342–3. doi:10.1038/180342a0. PMID 13464833.

[84] Furshpan; Potter, DD (1959). "Transmission at the giant motor synapses of the crayfish". The Journal of physiology. 145 (2): 289–325. PMC 1356828. PMID 13642302.

[85] Payton, B. W.; Bennett, M. V. L.; Pappas, G. D. (1969). "Permeability and structure of junctional membranes at an electrotonic synapse". Science. 166 (3913): 1641–3. doi:10.1126/science.166.3913.1641. PMID 5360587. {{cite journal}}: Unknown parameter |month= ignored (help)

[86] Chalcroft, J. P.; Bullivant, S (1970). "An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture". J. Cell Biol. 47 (1): 49–60. doi:10.1083/jcb.47.1.49. PMC 2108397. PMID 4935338. {{cite journal}}: Unknown parameter |month= ignored (help)

[87] Peracchia, C (1973). "Low resistance junctions in crayfish. II. Structural details and further evidence for intercellular channels by freeze-fracture and negative staining". J. Cell Biol. 57 (1): 54–65. PMC 2108965. PMID 4120610. {{cite journal}}: Unknown parameter |month= ignored (help)

[88] Gruijters, W (2003). "Are gap junction membrane plaques implicated in intercellular vesicle transfer?". Cell Biol. Int. 27 (9): 711–7. doi:10.1016/S1065-6995(03)00140-9. PMID 12972275.

[89] J Neurosci. 2010 Nov 10;30(45) 15277-85. Gap junction expression is required for normal chemical synapse formation. Todd KL, Kristan WB Jr, French KA.

[90] Goodenough, D. A.; Stoeckenius, W (1972). "THE ISOLATION OF MOUSE HEPATOCYTE GAP JUNCTIONS : Preliminary Chemical Characterization and X-Ray Diffraction". The Journal of Cell Biology. 54 (3): 646–56. doi:10.1083/jcb.54.3.646. PMC 2200277. PMID 4339819.

[91] Goodenough, D. A. (1974). "BULK ISOLATION OF MOUSE HEPATOCYTE GAP JUNCTIONS : Characterization of the Principal Protein, Connexin". The Journal of Cell Biology. 61 (2): 557–63. doi:10.1083/jcb.61.2.557. PMC 2109294. PMID 4363961.

[92] Kumar, N. M.; Gilula, NB (1986). "Cloning and characterization of human and rat liver cDNAs coding for a gap junction protein". The Journal of Cell Biology. 103 (3): 767–76. doi:10.1083/jcb.103.3.767. PMC 2114303. PMID 2875078.

[93] J Cell Biol. 1970 Dec;47(3) 666-88.The ultrastructure of the nexus. A correlated thin-section and freeze-cleave study. McNutt NS, Weinstein RS.

[94] Chalcroft, J. P.; Bullivant, S (1970). "AN INTERPRETATION OF LIVER CELL MEMBRANE AND JUNCTION STRUCTURE BASED ON OBSERVATION OF FREEZE-FRACTURE REPLICAS OF BOTH SIDES OF THE FRACTURE". The Journal of Cell Biology. 47 (1): 49–60. doi:10.1083/jcb.47.1.49. PMC 2108397. PMID 4935338.

[95] Young; Cohn, ZA; Gilula, NB (1987). "Functional assembly of gap junction conductance in lipid bilayers: demonstration that the major 27 kd protein forms the junctional channel". Cell. 48 (5): 733–43. doi:10.1016/0092-8674(87)90071-7. PMID 3815522.

[96] Nicholson; Gros, DB; Kent, SB; Hood, LE; Revel, JP (1985). "The Mr 28,000 gap junction proteins from rat heart and liver are different but related". The Journal of Biological Chemistry. 260 (11): 6514–7. PMID 2987225.

[97] Beyer, E. C.; Paul, DL; Goodenough, DA (1987). "Connexin43: a protein from rat heart homologous to a gap junction protein from liver". The Journal of Cell Biology. 105 (6 Pt 1): 2621–9. doi:10.1083/jcb.105.6.2621. PMC 2114703. PMID 2826492.

[98] Kistler, J; Kirkland, B; Bullivant, S (1985). "Identification of a 70,000-D protein in lens membrane junctional domains". The Journal of Cell Biology. 101 (1): 28–35. doi:10.1083/jcb.101.1.28. PMC 2113615. PMID 3891760.

[99] Three types of gap junctions interconnecting intestinal epithelial cells visualized by freeze-etching. Staehelin LA" Proc Natl Acad Sci U S A 1972 May;69(5) 1318-21.

[100] Gruijters, WTM; Kistler, J; Bullivant, S; Goodenough, DA (1987). "Immunolocalization of MP70 in lens fiber 16-17-nm intercellular junctions". The Journal of Cell Biology. 104 (3): 565–72. doi:10.1083/jcb.104.3.565. PMC 2114558. PMID 3818793.

[101] Gruijters, WTM; Kistler, J; Bullivant, S (1987). "Formation, distribution and dissociation of intercellular junctions in the lens". Journal of Cell Science. 88 (3): 351–9. PMID 3448099.

[Gruijters,_WTM_1989_509–13-102] Gruijters, WTM (1989). "A non-connexon protein (MIP) is involved in eye lens gap-junction formation". Journal of Cell Science. 93 (3): 509–13. PMID 2691517.

[103] Robertson, JD (1963). "THE OCCURRENCE OF A SUBUNIT PATTERN IN THE UNIT MEMBRANES OF CLUB ENDINGS IN MAUTHNER CELL SYNAPSES IN GOLDFISH BRAINS". J. Cell Biol. 19 (1): 201–21. doi:10.1083/jcb.19.1.201. PMC 2106854. PMID 14069795. {{cite journal}}: Unknown parameter |month= ignored (help)

[104] Hand, AR; Gobel, S (1972). "The structural organization of the septate and gap junctions of Hydra". J. Cell Biol. 52 (2): 397–408. doi:10.1083/jcb.52.2.397. PMC 2108629. PMID 4109925. {{cite journal}}: Unknown parameter |month= ignored (help)

[105] STUDIES ON AN EPITHELIAL (GLAND) CELL JUNCTION : I. Modifications of Surface Membrane Permeability Werner R. Loewenstein, Yoshinobu Kanno J Cell Biol. 1964 September 1; 22(3) 565–586. PMCID

[106] Gruijters, WTM (2003). "Are gap junction membrane plaques implicated in intercellular vesicle transfer?". Cell Biology International. 27 (9): 711–7. doi:10.1016/S1065-6995(03)00140-9. PMID 12972275.

[107] Ozato-Sakurai N, Fujita A, Fujimoto T. "The distribution of phosphatidylinositol 4,5-bisphosphate in acinar cells of rat pancreas revealed with the freeze-fracture replica labeling method. PLoS One. 2011;6(8) e23567. Epub 2011 Aug 15.

[108] Decker, RS; Friend, DS (1974). "Assembly of gap junctions during amphibian neurulation". J. Cell Biol. 62 (1): 32–47. doi:10.1083/jcb.62.1.32. PMC 2109180. PMID 4135001. {{cite journal}}: Unknown parameter |month= ignored (help)

[109] Decker, RS (1976). "Hormonal regulation of gap junction differentiation". J. Cell Biol. 69 (3): 669–85. doi:10.1083/jcb.69.3.669. PMC 2109697. PMID 1083855. {{cite journal}}: Unknown parameter |month= ignored (help)

[110] Proc Natl Acad Sci U S A. 2002 Aug 6;99(16) 10446-51. Epub 2002 Jul 29. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM.

[111] PLoS One. 2011;6(10) e26379. Epub 2011 Oct 14. Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics. Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C. Source Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

[112] Meyer, R; Malewicz, B; Baumann, WJ; Johnson, RG (1990). "Increased gap junction assembly between cultured cells upon cholesterol supplementation". J. Cell. Sci. 96 (2): 231–8. PMID 1698798. {{cite journal}}: Unknown parameter |month= ignored (help)

[113] Johnson, R. G.; Reynhout, J. K.; Tenbroek, E. M.; Quade, B. J.; Yasumura, T.; Davidson, K. G. V.; Sheridan, J. D.; Rash, J. E. (2012). "Gap junction assembly: roles for the formation plaque and regulation by the C-terminus of connexin43". Mol. Biol. Cell. 23 (1): 71–86. doi:10.1091/mbc.E11-02-0141. PMC 3248906. PMID 22049024. {{cite journal}}: Unknown parameter |month= ignored (help)

[114] Locke, Darren; Harris, Andrew L (2009). "Connexin channels and phospholipids: association and modulation". BMC Biol. 7: 52. doi:10.1186/1741-7007-7-52. PMC 2733891. PMID 19686581.{{cite journal}}: CS1 maint: unflagged free DOI (link)

[Naomi_Kamasawa_PMC-115] Connexin45-containing neuronal gap junctions in rodent retina also contain connexin36 in both apposing hemiplaques, forming bi-homotypic gap junctions, with scaffolding contributed by zonula occludens-1 Xinbo Li, Naomi Kamasawa, Cristina Ciolofan, Carl O. Olson, Shijun Lu, Kimberly G.V. Davidson, Thomas Yasumura, Ryuichi Shigemoto, John E. Rash, James I. Nagy J Neurosci. Author manuscript; available in PMC 2009 March 24.Published in final edited form as: J Neurosci. 2008 September 24; 28(39) 9769–9789. doi: 10.1523/JNEUROSCI.2137-08.2008 PMCID: PMC2638127

[116] The Distribution of Phosphatidylinositol 4,5-Bisphosphate in Acinar Cells of Rat Pancreas Revealed with the Freeze-Fracture Replica Labeling Method Nami Ozato-Sakurai, Akikazu Fujita, Toyoshi Fujimoto PLoS One. 2011; 6(8) e23567. Published online 2011 August 15. doi: 10.1371/journal.pone.0023567 PMCID: PMC3156236

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@@ Line 40: / Line 40: @@
 ==Properties of connexon channel pairs==
-[[File:Validation of the dye diffusion assay performed with the flattened cochlear preparation.png|right|thumb|Examples of dye injected into one cell moving into neighboring cells via gap junctions <ref>{{cite journal | pmid = 19116647 | doi=10.1371/journal.pone.0004088 | pmc=2605248 | volume=3 | issue=12 | title=Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice | year=2008 | journal=PLoS ONE | pages=e4088}}</ref>]]
+[[File:Validation of the dye diffusion assay performed with the flattened cochlear preparation.png|right|thumb|Examples of dye injected into one cell moving into neighboring cells via gap junctions <ref>{{cite journal | pmid = 19116647 | doi=10.1371/journal.pone.0004088 | pmc=2605248 | volume=3 | issue=12 | title=Gap junction mediated intercellular metabolite transfer in the cochlea is compromised in connexin30 null mice | year=2008 | journal=PLoS ONE | pages=e4088 | editor1-last = Schiffmann | editor1-first = Raphael | last1 = Chang | first1 = Qing | last2 = Tang | first2 = Wenxue | last3 = Ahmad | first3 = Shoeb | last4 = Zhou | first4 = Binfei | last5 = Lin | first5 = Xi}}</ref>]]
 # Allows for direct electrical communication between cells, although different connexin subunits can impart different single channel conductances, from about 30 pS to 500 pS.
 # Allows for chemical communication between cells, through the transmission of small [[second messenger]]s, such as [[inositol triphosphate]] (IP<sub>3</sub>) and calcium ([[Ca2+|Ca<sup>2+</sup>]]),<ref name="mbc"/> although different connexin subunits can impart different selectivity for particular small molecules.
-# Generally allows transmembrane movement of molecules smaller than 485 [[Atomic mass unit|Daltons]]<ref>{{cite journal | last1 = Hu | first1 = X | last2 = Dahl | first2 = G  | year = 1999 | title = Exchange of conductance and gating properties between gap junction hemichannels | url = | journal = FEBS Lett | volume = 451 | issue = | pages = 113–117 }}</ref> (1,100 Daltons through invertebrate gap junctions<ref>Loewenstein WR (1966) Permeability of membrane junctions. Ann N Y
+# Generally allows transmembrane movement of molecules smaller than 485 [[Atomic mass unit|Daltons]]<ref>{{cite journal | last1 = Hu | first1 = X | last2 = Dahl | first2 = G  | year = 1999 | title = Exchange of conductance and gating properties between gap junction hemichannels | url = | journal = FEBS Lett | volume = 451 | issue = 2| pages = 113–117 | doi = 10.1016/S0014-5793(99)00558-X | pmid = 10371149 }}</ref> (1,100 Daltons through invertebrate gap junctions<ref>Loewenstein WR (1966) Permeability of membrane junctions. Ann N Y
 Acad Sci 137:441–472.</ref>), although different connexin subunits may impart different pore sizes and different charge selectivity. Large biomolecules, for example, [[nucleic acid]] and [[protein]], are precluded from cytoplasmic transfer between cells through gap junction connexin channels.
 # Ensures that molecules and current passing through the gap junction do not leak into the intercellular space.
@@ Line 54: / Line 54: @@
 ==Occurrence and Distribution==
-Gap Junctions have been observed in various animal organs and tissues where cells contact each other. From the 1950s to 1970s they were detected in crayfish nerves,<ref>{{cite journal | pmid = 13037850 | volume=82 | issue=2 | title=Ultrastructure of two invertebrate synapses | year=1953 | month=February | pages=219–23}}</ref> rat pancreas, liver, adrenal cortex, epididymis, duodenum, muscle,<ref>Variations in tight and gap junctions in mammalian tissues.Friend DS, Gilula NB" ''J Cell Biol'' 1972 Jun;53(3) 758-76.</ref> Daphnia hepatic caecum,<ref>{{cite journal | last1 = Hudspeth | first1 = AJ | last2 = Revel | first2 = JP.  | year = 1971 | month = Jul | title = Coexistence of gap and septate junctions in an invertebrate epithelium | url = | journal = J Cell Biol. | volume = 50 | issue = 1| pages = 92–101 }}</ref> Hydra muscle,<ref>The structural organization of the septate and gap junctions of Hydra.Hand AR, Gobel S" ''J Cell Biol'' 1972 Feb;52(2) 397-408.</ref> monkey retina,<ref>{{cite journal | last1 = Raviola | first1 = E | last2 = Gilula | first2 = NB.  | year = 1973 | month = Jun | title = Gap junctions between photoreceptor cells in the vertebrate retina | url = | journal = Proc Natl Acad Sci U S A. | volume = 70 | issue = 6| pages = 1677–81 }}</ref> rabbit cornea,<ref> Kreutziger GO. "Lateral membrane morphology and gap junction structure in rabbit corneal endothelium.  ''Exp Eye Res.'' 1976 Sep;23(3) 285-93. PMC433571</ref> fish blastoderm,<ref>J Cell Biol. 1971 March 1; 48(3)  455–472. PMCID: PMC2108114 DIFFERENTIATION OF THE JUNCTIONAL COMPLEX OF SURFACE CELLS IN THE DEVELOPING FUNDULUS BLASTODERM Thomas L. Lentz and J. P. Trinkaus</ref> frog embryos,<ref name="ReferenceA">J Cell Biol. 1974 Jul;62(1) 32-47.Assembly of gap junctions during amphibian neurulation. Decker RS, Friend DS.</ref> rabbit ovary,<ref>{{cite journal | last1 = Albertini | first1 = DF | last2 = Anderson | first2 = E.  | year = 1974 | month = Oct | title = The appearance and structure of intercellular connections during the ontogeny of the rabbit ovarian follicle with particular reference to gap junctions | url = | journal = J Cell Biol | volume = 63 | issue = 1| pages = 234–50 }}</ref> re-aggregating cells,<ref>Proc Natl Acad Sci U S A. 1974 Nov;71(11) 4536-40. Gap junction formation between reaggregated Novikoff hepatoma cells. Johnson R, Hammer M, Sheridan J, Revel JP.</ref><ref>{{cite journal | last1 = Knudsen | first1 = KA | last2 = Horwitz | first2 = AF.  | year = 1978 | title = Toward a mechanism of myoblast fusion | url = | journal = Prog Clin Biol Res. | volume = 23 | issue = | pages = 563–8 }}</ref> cockroach hemocyte capsules,<ref>Tissue Cell. 1975;7(3) 575-85. Inverted gap and other cell junctions in cockroach hemocyte capsules: a thin section and freeze-fracture study. Baerwald RJ.</ref> rabbit skin,<ref>Cancer Res. 1975 Feb;35(2) 364-9. Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, Keratoacanthoma. Prutkin L.</ref> chick embryos,<ref>{{cite journal | last1 = Bellairs | first1 = R | last2 = Breathnach | first2 = AS | last3 = Gross | first3 = M.  | year = 1975 | month = Sep | title = Freeze-fracture replication of junctional complexes in unincubated and incubated chick embryos | url = | journal = Cell Tissue Res. | volume = 162 | issue = 2| pages = 235–52 }}</ref> human islet of Langerhans,<ref>''J Clin Endocrinol Metab.'' 1975 Nov;41(5) 841-4.Cell contacts in human islets of Langerhans. Orci L, Malaisse-Lagae F, Amherdt M, Ravazzola M, Weisswange A, Dobbs R, Perrelet A, Unger R.</ref> goldfish and hamster pressure sensing acoustico-vestibular receptors,<ref>''J Neurocytol.'' 1977 Feb;6(1) 1-12. Gap junctions between the supporting cells in some acoustico-vestibular receptors. Hama K, Saito K.</ref> lamprey and tunicate heart,<ref>{{cite journal | pmid = 870202 | volume=178 | issue=4 | title=Gap junctions in the cardiac muscle cells of the lamprey | year=1977 | month=March | journal=Cell Tissue Res. | pages=477–82}}</ref><ref>{{cite journal | pmid = 858161 | volume=179 | issue=2 | title=Fine structure of the gap junction in the tunicate heart | year=1977 | month=April | journal=Cell Tissue Res. | pages=169–75}}</ref> rat seminiferous tubules,<ref>Intercellular junctional complexes of the rat seminiferous tubules: a freeze-fracture study. McGinley D, Posalaky Z, Provaznik M. Anat Rec. 1977 Oct;189(2) 211-31.</ref> myometrium,<ref>{{cite journal | pmid = 727239 | volume=235 | issue=5 | title=Possible role of gap junctions in activation of myometrium during parturition | year=1978 | month=November | journal=Am. J. Physiol. | pages=C168–79}}</ref> eye lens <ref>{{cite journal | pmid = 511455 | volume=18 | issue=11 | title=Lens gap junctions: a structural hypothesis for nonregulated low-resistance intercellular pathways | year=1979 | month=November | journal=Invest. Ophthalmol. Vis. Sci. | pages=1104–22}}</ref> and cephalopod digestive epithelium.<ref>{{cite journal | pmid = 7414602 | volume=12 | issue=2 | title=Junctional structures in digestive epithelia of a cephalopod | year=1980 | journal=Tissue Cell | pages=395–404 | doi=10.1016/0040-8166(80)90013-0}}</ref> Since the 1970s gap junctions have continued to been found in nearly all animal cells that touch each other. By the 1990s new technology such as confocal microscopy allowed more rapid survey of large areas of tissue. Since the 1970s even tissues that were traditionally considered to possibly have isolated cells such as bone showed that the cells were still connected with gap junctions, however tenuously.<ref>Anat Embryol (Berl). 1993 Apr;187(4) 343-52. The incidence and size of gap junctions between the bone cells in rat calvaria. Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, Green C</ref> Gap junctions appear to be in all animal organs and tissues and it will be interesting to find exceptions to this other than cells not normally in contact with neighboring cells. Adult skeletal muscle is a possible exception. It may be argued that if present in skeletal muscle gap junctions might propagate contractions in an arbitrary way among cells making up the muscle. At least in some cases this may not be the case as shown in other muscle types that do have gap junctions.<ref>{{cite journal | pmid =   15679888 | doi=10.1186/1475-925X-4-7 | pmc=549032 | volume=4 | issue=1 | title=Gap-junction channels inhibit transverse propagation in cardiac muscle | year=2005 | journal=Biomed Eng Online | pages=7}}</ref> An indication of what results from reduction or absence of gap junctions may be indicated by analysis of cancers <ref>J Membr Biol. 1977 Jun 3;34(1) 39-54.Intercellular communication and tissue growth: IX. Junctional membrane structure of hybrids between communication-competent and communication-incompetent cells.Larsen WJ, Azarnia R, Loewenstein WR.</ref><ref>''Proc Natl Acad Sci U S A.'' 1977 Oct;74(10) 4476-80. Comparison of contact-mediated communication in normal and transformed human cells in culture.Corsaro CM, Migeon BR.</ref><ref>{{cite journal | pmid = 11145599 | volume=142 | issue=1 | title=Developmental exposure to estrogens alters epithelial cell adhesion and gap junction proteins in the adult rat prostate | year=2001 | month=January | journal=Endocrinology | pages=359–69}}</ref> or the aging process.<ref>{{cite journal | pmid = 761600 | volume=119 | issue=1 | title=Development of the aging cell surface. Reduction of gap junction-mediated metabolic cooperation with progressive subcultivation of human embryo fibroblasts (IMR-90) | year=1979 | month=March | journal=Exp. Cell Res. | pages=127–43 | doi=10.1016/0014-4827(79)90342-2}}</ref>
+Gap Junctions have been observed in various animal organs and tissues where cells contact each other. From the 1950s to 1970s they were detected in crayfish nerves,<ref>{{cite journal | pmid = 13037850 | volume=82 | issue=2 | title=Ultrastructure of two invertebrate synapses | year=1953 | month=February | pages=219–23 | last1 = Robertson | first1 = JD | journal = Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine}}</ref> rat pancreas, liver, adrenal cortex, epididymis, duodenum, muscle,<ref>Variations in tight and gap junctions in mammalian tissues.Friend DS, Gilula NB" ''J Cell Biol'' 1972 Jun;53(3) 758-76.</ref> Daphnia hepatic caecum,<ref>{{cite journal | last1 = Hudspeth | first1 = AJ | last2 = Revel | first2 = JP.  | year = 1971 | month = Jul | title = Coexistence of gap and septate junctions in an invertebrate epithelium | url = | journal = J Cell Biol. | volume = 50 | issue = 1| pages = 92–101 | doi = 10.1083/jcb.50.1.92 | pmid = 5563454 | pmc = 2108432 }}</ref> Hydra muscle,<ref>The structural organization of the septate and gap junctions of Hydra.Hand AR, Gobel S" ''J Cell Biol'' 1972 Feb;52(2) 397-408.</ref> monkey retina,<ref>{{cite journal | last1 = Raviola | first1 = E | last2 = Gilula | first2 = NB.  | year = 1973 | month = Jun | title = Gap junctions between photoreceptor cells in the vertebrate retina | url = | journal = Proc Natl Acad Sci U S A. | volume = 70 | issue = 6| pages = 1677–81 | bibcode = 1973PNAS...70.1677R | doi = 10.1073/pnas.70.6.1677 | pmid = 4198274 | pmc = 433571 }}</ref> rabbit cornea,<ref> Kreutziger GO. "Lateral membrane morphology and gap junction structure in rabbit corneal endothelium.  ''Exp Eye Res.'' 1976 Sep;23(3) 285-93. PMC433571</ref> fish blastoderm,<ref>J Cell Biol. 1971 March 1; 48(3)  455–472. PMCID: PMC2108114 DIFFERENTIATION OF THE JUNCTIONAL COMPLEX OF SURFACE CELLS IN THE DEVELOPING FUNDULUS BLASTODERM Thomas L. Lentz and J. P. Trinkaus</ref> frog embryos,<ref name="ReferenceA">J Cell Biol. 1974 Jul;62(1) 32-47.Assembly of gap junctions during amphibian neurulation. Decker RS, Friend DS.</ref> rabbit ovary,<ref>{{cite journal | last1 = Albertini | first1 = DF | last2 = Anderson | first2 = E.  | year = 1974 | month = Oct | title = The appearance and structure of intercellular connections during the ontogeny of the rabbit ovarian follicle with particular reference to gap junctions | url = | journal = J Cell Biol | volume = 63 | issue = 1| pages = 234–50 | doi = 10.1083/jcb.63.1.234 | pmid = 4417791 | pmc = 2109337 }}</ref> re-aggregating cells,<ref>Proc Natl Acad Sci U S A. 1974 Nov;71(11) 4536-40. Gap junction formation between reaggregated Novikoff hepatoma cells. Johnson R, Hammer M, Sheridan J, Revel JP.</ref><ref>{{cite journal | last1 = Knudsen | first1 = KA | last2 = Horwitz | first2 = AF.  | year = 1978 | title = Toward a mechanism of myoblast fusion | url = | journal = Prog Clin Biol Res. | volume = 23 | issue = | pages = 563–8 | pmid = 96453 }}</ref> cockroach hemocyte capsules,<ref>Tissue Cell. 1975;7(3) 575-85. Inverted gap and other cell junctions in cockroach hemocyte capsules: a thin section and freeze-fracture study. Baerwald RJ.</ref> rabbit skin,<ref>Cancer Res. 1975 Feb;35(2) 364-9. Mucous metaplasia and gap junctions in the vitamin A acid-treated skin tumor, Keratoacanthoma. Prutkin L.</ref> chick embryos,<ref>{{cite journal | last1 = Bellairs | first1 = R | last2 = Breathnach | first2 = AS | last3 = Gross | first3 = M.  | year = 1975 | month = Sep | title = Freeze-fracture replication of junctional complexes in unincubated and incubated chick embryos | url = | journal = Cell Tissue Res. | volume = 162 | issue = 2| pages = 235–52 | doi = 10.1007/BF00209209 | pmid = 1237352 }}</ref> human islet of Langerhans,<ref>''J Clin Endocrinol Metab.'' 1975 Nov;41(5) 841-4.Cell contacts in human islets of Langerhans. Orci L, Malaisse-Lagae F, Amherdt M, Ravazzola M, Weisswange A, Dobbs R, Perrelet A, Unger R.</ref> goldfish and hamster pressure sensing acoustico-vestibular receptors,<ref>''J Neurocytol.'' 1977 Feb;6(1) 1-12. Gap junctions between the supporting cells in some acoustico-vestibular receptors. Hama K, Saito K.</ref> lamprey and tunicate heart,<ref>{{cite journal | pmid = 870202 | volume=178 | issue=4 | title=Gap junctions in the cardiac muscle cells of the lamprey | year=1977 | month=March | journal=Cell Tissue Res. | pages=477–82 | last1 = Shibata | first1 = Y | last2 = Yamamoto | first2 = T}}</ref><ref>{{cite journal | pmid = 858161 | volume=179 | issue=2 | title=Fine structure of the gap junction in the tunicate heart | year=1977 | month=April | journal=Cell Tissue Res. | pages=169–75 | last1 = Lorber | first1 = V | last2 = Rayns | first2 = DG}}</ref> rat seminiferous tubules,<ref>Intercellular junctional complexes of the rat seminiferous tubules: a freeze-fracture study. McGinley D, Posalaky Z, Provaznik M. Anat Rec. 1977 Oct;189(2) 211-31.</ref> myometrium,<ref>{{cite journal | pmid = 727239 | volume=235 | issue=5 | title=Possible role of gap junctions in activation of myometrium during parturition | year=1978 | month=November | journal=Am. J. Physiol. | pages=C168–79 | last1 = Garfield | first1 = RE | last2 = Sims | first2 = SM | last3 = Kannan | first3 = MS | last4 = Daniel | first4 = EE}}</ref> eye lens <ref>{{cite journal | pmid = 511455 | volume=18 | issue=11 | title=Lens gap junctions: a structural hypothesis for nonregulated low-resistance intercellular pathways | year=1979 | month=November | journal=Invest. Ophthalmol. Vis. Sci. | pages=1104–22 | last1 = Goodenough | first1 = DA}}</ref> and cephalopod digestive epithelium.<ref>{{cite journal | pmid = 7414602 | volume=12 | issue=2 | title=Junctional structures in digestive epithelia of a cephalopod | year=1980 | journal=Tissue Cell | pages=395–404 | doi=10.1016/0040-8166(80)90013-0 | last1 = Boucaud-Camou | first1 = Eve}}</ref> Since the 1970s gap junctions have continued to been found in nearly all animal cells that touch each other. By the 1990s new technology such as confocal microscopy allowed more rapid survey of large areas of tissue. Since the 1970s even tissues that were traditionally considered to possibly have isolated cells such as bone showed that the cells were still connected with gap junctions, however tenuously.<ref>Anat Embryol (Berl). 1993 Apr;187(4) 343-52. The incidence and size of gap junctions between the bone cells in rat calvaria. Jones SJ, Gray C, Sakamaki H, Arora M, Boyde A, Gourdie R, Green C</ref> Gap junctions appear to be in all animal organs and tissues and it will be interesting to find exceptions to this other than cells not normally in contact with neighboring cells. Adult skeletal muscle is a possible exception. It may be argued that if present in skeletal muscle gap junctions might propagate contractions in an arbitrary way among cells making up the muscle. At least in some cases this may not be the case as shown in other muscle types that do have gap junctions.<ref>{{cite journal | pmid =   15679888 | doi=10.1186/1475-925X-4-7 | pmc=549032 | volume=4 | issue=1 | title=Gap-junction channels inhibit transverse propagation in cardiac muscle | year=2005 | journal=Biomed Eng Online | pages=7 | last1 =   Sperelakis | first1 =   Nicholas | last2 =   Ramasamy | first2 =   Lakshminarayanan}}</ref> An indication of what results from reduction or absence of gap junctions may be indicated by analysis of cancers <ref>J Membr Biol. 1977 Jun 3;34(1) 39-54.Intercellular communication and tissue growth: IX. Junctional membrane structure of hybrids between communication-competent and communication-incompetent cells.Larsen WJ, Azarnia R, Loewenstein WR.</ref><ref>''Proc Natl Acad Sci U S A.'' 1977 Oct;74(10) 4476-80. Comparison of contact-mediated communication in normal and transformed human cells in culture.Corsaro CM, Migeon BR.</ref><ref>{{cite journal | pmid = 11145599 | volume=142 | issue=1 | title=Developmental exposure to estrogens alters epithelial cell adhesion and gap junction proteins in the adult rat prostate | year=2001 | month=January | journal=Endocrinology | pages=359–69 | doi = 10.1210/en.142.1.359 | last1 = Habermann | first1 = H | last2 = Chang | first2 = WY | last3 = Birch | first3 = L | last4 = Mehta | first4 = P | last5 = Prins | first5 = GS}}</ref> or the aging process.<ref>{{cite journal | pmid = 761600 | volume=119 | issue=1 | title=Development of the aging cell surface. Reduction of gap junction-mediated metabolic cooperation with progressive subcultivation of human embryo fibroblasts (IMR-90) | year=1979 | month=March | journal=Exp. Cell Res. | pages=127–43 | doi=10.1016/0014-4827(79)90342-2 | last1 = Kelley | first1 = Robert O. | last2 = Vogel | first2 = Kathryn G. | last3 = Crissman | first3 = Harry A. | last4 = Lujan | first4 = Christopher J. | last5 = Skipper | first5 = Betty E.}}</ref>
 ==Functions==
@@ Line 60: / Line 60: @@
 ===Embryonic, Organ and Tissue Development===
-In the 1980s more subtle but no less important roles of gap junction communication have been investigated. It was discovered that gap junction communication could be disrupted by adding anti-connexin antibodies into embryonic cells.<ref>{{cite journal | pmid = 6088995 | volume=311 | issue=5982 | title=Antibodies to gap-junctional protein selectively disrupt junctional communication in the early amphibian embryo | year=1984 | journal=Nature | pages=127–31}}</ref><ref>{{cite journal | pmid = 3030673 | volume=125 | title=The use of antibodies to gap junction protein to explore the role of gap junctional communication during development | year=1987 | journal=Ciba Found. Symp. | pages=154–67}}</ref> Embryos with areas of blocked gap junctions failed to develop normally. The mechanism by which antibodies blocked the gap junctions was unclear but systematic studies were undertaken to elucidate the mechanism.<ref>{{cite journal | pmid = 8661989 | volume=150 | issue=3 | title=Effect of antipeptide antibodies directed against three domains of connexin43 on the gap junctional permeability of cultured heart cells | year=1996 | month=April | journal=J. Membr. Biol. | pages=243–53}}</ref><ref>{{cite journal | pmid = 9700496 | volume=24 | issue=1 | title=Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes | year=1998 | month=September | journal=Glia | pages=141–54}}</ref> Refinement of these studies showed that gap junctions appeared to be key to development of cell polarity <ref name="ReferenceB">''PLoS One.'' 2011;6(10) e26379. Epub 2011 Oct 14. Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics.Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C.</ref> and the left/right symmetry/asymmetry in animals.<ref>{{cite journal | pmid =  9806775 | doi=10.1006/dbio.1998.9024 | volume=203 | issue=1 | title=Gap junctions are involved in the early generation of left-right asymmetry | year=1998 | month=November | journal=Dev. Biol. | pages=90–105}}</ref><ref>{{cite journal | pmid = 10518488 | volume=126 | issue=21 | title=Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node | year=1999 | month=November | journal=Development | pages=4703–14}}</ref> While signaling that determines the position of body organs appears to rely on gap junctions so does the more fundamental differentiation of cells at later stages of embryonic development.<ref>{{cite journal | pmid = 10079512 | doi=10.1002/(SICI)1520-6408(1999)24:1/2&lt;69::AID-DVG8&gt;3.0.CO;2-M | volume=24 | issue=1-2 | title=Gap junction blockage interferes with neuronal and astroglial differentiation of mouse P19 embryonal carcinoma cells | year=1999 | journal=Dev. Genet. | pages=69–81}}</ref><ref>{{cite journal | pmid = 10192774 | doi=10.1006/exnr.1998.6950 | volume=156 | issue=1 | title=The effects of gap junction blockage on neuronal differentiation of human NTera2/clone D1 cells | year=1999 | month=March | journal=Exp. Neurol. | pages=16–32}}</ref><ref>{{cite journal | pmid = 10666026 | volume=278 | issue=2 | title=Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication | year=2000 | month=February | journal=Am. J. Physiol., Cell Physiol. | pages=C315–22}}</ref><ref>{{cite journal | pmid =  12826585 | doi=10.1095/biolreprod.103.016360 | volume=69 | issue=5 | title=Requirement of gap junctional intercellular communication for human villous trophoblast differentiation | year=2003 | month=November | journal=Biol. Reprod. | pages=1472–80}}</ref><ref>{{cite journal | pmid =  12893812 | doi=10.1242/jcs.00656 | volume=116 | issue=Pt 17 | title=ECM-induced gap junctional communication enhances mammary epithelial cell differentiation | year=2003 | month=September | journal=J. Cell. Sci. | pages=3531–41}}</ref>
+In the 1980s more subtle but no less important roles of gap junction communication have been investigated. It was discovered that gap junction communication could be disrupted by adding anti-connexin antibodies into embryonic cells.<ref>{{cite journal | pmid = 6088995 | volume=311 | issue=5982 | title=Antibodies to gap-junctional protein selectively disrupt junctional communication in the early amphibian embryo | year=1984 | journal=Nature | pages=127–31 | bibcode = 1984Natur.311..127W | author1 = Warner | first1 = Anne E. | last2 = Guthrie | first2 = Sarah C. | last3 = Gilula | first3 = Norton B. | doi = 10.1038/311127a0}}</ref><ref>{{cite journal | pmid = 3030673 | volume=125 | title=The use of antibodies to gap junction protein to explore the role of gap junctional communication during development | year=1987 | journal=Ciba Found. Symp. | pages=154–67 | last1 = Warner | first1 = AE}}</ref> Embryos with areas of blocked gap junctions failed to develop normally. The mechanism by which antibodies blocked the gap junctions was unclear but systematic studies were undertaken to elucidate the mechanism.<ref>{{cite journal | pmid = 8661989 | volume=150 | issue=3 | title=Effect of antipeptide antibodies directed against three domains of connexin43 on the gap junctional permeability of cultured heart cells | year=1996 | month=April | journal=J. Membr. Biol. | pages=243–53 | doi = 10.1007/s002329900048 | last1 = Bastide | first1 = B | last2 = Jarry-Guichard | first2 = T | last3 = Briand | first3 = JP | last4 = Délèze | first4 = J | last5 = Gros | first5 = D}}</ref><ref>{{cite journal | pmid = 9700496 | volume=24 | issue=1 | title=Visualization and functional blocking of gap junction hemichannels (connexons) with antibodies against external loop domains in astrocytes | year=1998 | month=September | journal=Glia | pages=141–54 | doi = 10.1002/(SICI)1098-1136(199809)24:1<141::AID-GLIA13>3.0.CO;2-R | last1 = Hofer | first1 = A | last2 = Dermietzel | first2 = R}}</ref> Refinement of these studies showed that gap junctions appeared to be key to development of cell polarity <ref name="ReferenceB">''PLoS One.'' 2011;6(10) e26379. Epub 2011 Oct 14. Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics.Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C.</ref> and the left/right symmetry/asymmetry in animals.<ref>{{cite journal | pmid =  9806775 | doi=10.1006/dbio.1998.9024 | volume=203 | issue=1 | title=Gap junctions are involved in the early generation of left-right asymmetry | year=1998 | month=November | journal=Dev. Biol. | pages=90–105 | last1 =  Levin | first1 =  Michael | last2 =  Mercola | first2 =  Mark}}</ref><ref>{{cite journal | pmid = 10518488 | volume=126 | issue=21 | title=Gap junction-mediated transfer of left-right patterning signals in the early chick blastoderm is upstream of Shh asymmetry in the node | year=1999 | month=November | journal=Development | pages=4703–14 | last1 = Levin | first1 = M | last2 = Mercola | first2 = M}}</ref> While signaling that determines the position of body organs appears to rely on gap junctions so does the more fundamental differentiation of cells at later stages of embryonic development.<ref>{{cite journal | pmid = 10079512 | doi=10.1002/(SICI)1520-6408(1999)24:1/2<69::AID-DVG8>3.0.CO;2-M | volume=24 | issue=1–2 | title=Gap junction blockage interferes with neuronal and astroglial differentiation of mouse P19 embryonal carcinoma cells | year=1999 | journal=Dev. Genet. | pages=69–81 | last1 = Bani-Yaghoub | first1 = Mahmud | last2 = Underhill | first2 = T. Michael | last3 = Naus | first3 = Christian C.G.}}</ref><ref>{{cite journal | pmid = 10192774 | doi=10.1006/exnr.1998.6950 | volume=156 | issue=1 | title=The effects of gap junction blockage on neuronal differentiation of human NTera2/clone D1 cells | year=1999 | month=March | journal=Exp. Neurol. | pages=16–32 | last1 = Bani-Yaghoub | first1 = Mahmud | last2 = Bechberger | first2 = John F. | last3 = Underhill | first3 = T.Michael | last4 = Naus | first4 = Christian C.G.}}</ref><ref>{{cite journal | pmid = 10666026 | volume=278 | issue=2 | title=Differentiation of human fetal osteoblastic cells and gap junctional intercellular communication | year=2000 | month=February | journal=Am. J. Physiol., Cell Physiol. | pages=C315–22 | last1 = Donahue | first1 = HJ | last2 = Li | first2 = Z | last3 = Zhou | first3 = Z | last4 = Yellowley | first4 = CE}}</ref><ref>{{cite journal | pmid =  12826585 | doi=10.1095/biolreprod.103.016360 | volume=69 | issue=5 | title=Requirement of gap junctional intercellular communication for human villous trophoblast differentiation | year=2003 | month=November | journal=Biol. Reprod. | pages=1472–80 | last1 =  Cronier | first1 =  L. | last2 =  Frendo | first2 =  JL | last3 =  Defamie | first3 =  N | last4 =  Pidoux | first4 =  G | last5 =  Bertin | first5 =  G | last6 =  Guibourdenche | first6 =  J | last7 =  Pointis | first7 =  G | last8 =  Malassine | first8 =  A}}</ref><ref>{{cite journal | pmid =  12893812 | doi=10.1242/jcs.00656 | volume=116 | issue=Pt 17 | title=ECM-induced gap junctional communication enhances mammary epithelial cell differentiation | year=2003 | month=September | journal=J. Cell. Sci. | pages=3531–41 | last1 =  El-Sabban | first1 =  M. E. | last2 =  Sfeir | first2 =  AJ | last3 =  Daher | first3 =  MH | last4 =  Kalaany | first4 =  NY | last5 =  Bassam | first5 =  RA | last6 =  Talhouk | first6 =  RS}}</ref>
-Gap junctions were also found to be responsible for the transmission of signals required for drugs to have an effect <ref>{{cite journal | pmid = 10523421 | pmc=2269589 | volume=520 | title=The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication | year=1999 | month=October | journal=J. Physiol. (Lond.) | pages=539–50 | issue=2}}</ref> and conversely some drugs were shown to block gap junction channels.<ref>{{cite journal | pmid =  11535816 | doi=10.1073/pnas.191206198 | pmc=58578 | volume=98 | issue=19 | title=Quinine blocks specific gap junction channel subtypes | year=2001 | month=September | journal=Proc. Natl. Acad. Sci. U.S.A. | pages=10942–7}}</ref>
+Gap junctions were also found to be responsible for the transmission of signals required for drugs to have an effect <ref>{{cite journal | pmid = 10523421 | pmc=2269589 | volume=520 | title=The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication | year=1999 | month=October | journal=J. Physiol. (Lond.) | pages=539–50 | issue=2 | doi = 10.1111/j.1469-7793.1999.00539.x | last1 = Chaytor | first1 = AT | last2 = Martin | first2 = PE | last3 = Evans | first3 = WH | last4 = Randall | first4 = MD | last5 = Griffith | first5 = TM}}</ref> and conversely some drugs were shown to block gap junction channels.<ref>{{cite journal | pmid =  11535816 | doi=10.1073/pnas.191206198 | pmc=58578 | volume=98 | issue=19 | title=Quinine blocks specific gap junction channel subtypes | year=2001 | month=September | journal=Proc. Natl. Acad. Sci. U.S.A. | pages=10942–7 | last1 =  Srinivas | first1 =  M. | last2 =  Hopperstad | first2 =  MG | last3 =  Spray | first3 =  DC}}</ref>
 ===Gap junctions and the "bystander effect"===
 ====Cell death====
-The "bystander effect" with its connotations of the innocent bystander being killed is also mediated by gap junctions. When cells are compromised due to disease or injury and start to die messages are transmitted to neighboring cells connected to the dying cell by gap junctions. This can cause the otherwise unaffected healthy bystander cells to also die.<ref>{{cite journal | pmid = 8186287 | doi=10.1089/hum.1993.4.6-725 | volume=4 | issue=6 | title=In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy | year=1993 | month=December | journal=Hum. Gene Ther. | pages=725–31}}</ref> The bystander effect is therefore important to consider in diseased cells which opened an avenue for more funding and a flourish of research.<ref>{{cite journal | pmid = 7945800 | volume=11 | issue=3 | title=Cancer gene therapy: a bystander effect using the gap junctional pathway | year=1994 | month=November | journal=Mol. Carcinog. | pages=127–30}}</ref><ref>{{cite journal | pmid = 7548276 | doi=10.1089/hum.1995.6.6-763 | volume=6 | issue=6 | title=The &quot;bystander effect&quot;: association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice | year=1995 | month=June | journal=Hum. Gene Ther. | pages=763–72}}</ref><ref>{{cite journal | pmid = 7479939 | pmc=40573 | volume=92 | issue=24 | title=The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro | year=1995 | month=November | journal=Proc. Natl. Acad. Sci. U.S.A. | pages=11071–5}}</ref><ref>{{cite journal |pmid=8929915 | volume=3 | issue=1 | title=Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro | year=1996 | month=January | journal=Gene Ther. | pages=85–92}}</ref><ref>{{cite journal | pmid = 8700844 | pmc=39867 | volume=93 | issue=5 | title=Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins | year=1996 | month=March | pages=1831–5}}</ref><ref>{{cite journal | pmid =  8622159 | doi=10.3171/jns.1996.84.5.0839 | volume=84 | issue=5 | title=Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy | year=1996 | month=May | journal=J. Neurosurg. | pages=839–45; discussion 846}}</ref><ref>{{cite journal |pmid=8665496 | volume=56 | issue=12 | title=Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells | year=1996 | month=June | journal=Cancer Res. | pages=2697–702}}</ref><ref>{{cite journal | pmid = 8986442 | volume=3 | issue=12 | title=Partial regression, yet incomplete eradication of mammary tumors in transgenic mice by retrovirally mediated HSVtk transfer 'in vivo' | year=1996 | month=December | journal=Gene Ther. | pages=1151–6}}</ref><ref>{{cite journal | pmid = 12014914 | doi=10.1006/exer.2002.1155 | volume=74 | issue=3 | title=Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect | year=2002 | month=March | journal=Exp. Eye Res. | pages=327–36}}</ref> Later the bystander effect was also researched with regard to cells damaged by radiation or mechanical injury and therefore wound healing.<ref>{{cite journal | pmid = 12194273 | volume=99 | issue=1-4 | title=Bystander effects: intercellular transmission of radiation damage signals | year=2002 | journal=Radiat Prot Dosimetry | pages=159–62}}</ref><ref>{{cite journal | pmid = 12194291 | volume=99 | issue=1-4 | title=Genotoxic damage in non-irradiated cells: contribution from the bystander effect | year=2002 | journal=Radiat Prot Dosimetry | pages=227–32}}</ref><ref>{{cite journal | pmid = 12556327 | volume=79 | issue=1 | title=Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review | year=2003 | month=January | journal=Int. J. Radiat. Biol. | pages=15–25}}</ref><ref>{{cite journal | pmid = 14617290 | volume=11 | issue=6 | title=Role for gap junctional intercellular communications in wound repair | year=2003 | journal=Wound Repair Regen | pages=481–9}}</ref><ref>{{cite journal | pmid = 15927148 | doi=10.1016/j.bjps.2004.12.022 | volume=58 | issue=5 | title=Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury | year=2005 | month=July | journal=Br J Plast Surg | pages=658–67}}</ref> Disease also seems to have an effect on the ability of gap junctions to fulfill their roles in wound healing.<ref>{{cite journal | pmid =  17717278 | doi=10.2337/db07-0613 | volume=56 | issue=11 | title=Abnormal connexin expression underlies delayed wound healing in diabetic skin | year=2007 | month=November | journal=Diabetes | pages=2809–17}}</ref><ref>{{cite journal | pmid = 9550065 | volume=9 | issue=1 | title=Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching | year=1997 | journal=Pract Periodontics Aesthet Dent | pages=117–28}}</ref>
+The "bystander effect" with its connotations of the innocent bystander being killed is also mediated by gap junctions. When cells are compromised due to disease or injury and start to die messages are transmitted to neighboring cells connected to the dying cell by gap junctions. This can cause the otherwise unaffected healthy bystander cells to also die.<ref>{{cite journal | pmid = 8186287 | doi=10.1089/hum.1993.4.6-725 | volume=4 | issue=6 | title=In vitro evidence that metabolic cooperation is responsible for the bystander effect observed with HSV tk retroviral gene therapy | year=1993 | month=December | journal=Hum. Gene Ther. | pages=725–31 | last1 = Li Bi | first1 = Wan | last2 = Parysek | first2 = Linda M. | last3 = Warnick | first3 = Ronald | last4 = Stambrook | first4 = Peter J.}}</ref> The bystander effect is therefore important to consider in diseased cells which opened an avenue for more funding and a flourish of research.<ref>{{cite journal | pmid = 7945800 | volume=11 | issue=3 | title=Cancer gene therapy: a bystander effect using the gap junctional pathway | year=1994 | month=November | journal=Mol. Carcinog. | pages=127–30 | doi = 10.1002/mc.2940110302 | last1 = Pitts | first1 = JD}}</ref><ref>{{cite journal | pmid = 7548276 | doi=10.1089/hum.1995.6.6-763 | volume=6 | issue=6 | title=The &quot;bystander effect&quot;: association of U-87 cell death with ganciclovir-mediated apoptosis of nearby cells and lack of effect in athymic mice | year=1995 | month=June | journal=Hum. Gene Ther. | pages=763–72 | last1 = Colombo | first1 = Bruno M. | last2 = Benedetti | first2 = Sara | last3 = Ottolenghi | first3 = Sergio | last4 = Mora | first4 = Marina | last5 = Pollo | first5 = Bianca | last6 = Poli | first6 = Giorgio | last7 = Finocchiaro | first7 = Gaetano}}</ref><ref>{{cite journal | pmid = 7479939 | pmc=40573 | volume=92 | issue=24 | title=The extent of heterocellular communication mediated by gap junctions is predictive of bystander tumor cytotoxicity in vitro | year=1995 | month=November | journal=Proc. Natl. Acad. Sci. U.S.A. | pages=11071–5 | bibcode = 1995PNAS...9211071F | author1 = Fick | first1 = James | last2 = Barker | first2 = Fred G. | last3 = Dazin | first3 = Paul | last4 = Westphale | first4 = Eileen M. | last5 = Beyer | first5 = Eric C. | last6 = Israel | first6 = Mark A. | doi = 10.1073/pnas.92.24.11071}}</ref><ref>{{cite journal |pmid=8929915 | volume=3 | issue=1 | title=Gap junctions play a role in the 'bystander effect' of the herpes simplex virus thymidine kinase/ganciclovir system in vitro | year=1996 | month=January | journal=Gene Ther. | pages=85–92 |last1=Elshami |first1=AA |last2=Saavedra |first2=A |last3=Zhang |first3=H |last4=Kucharczuk |first4=JC |last5=Spray |first5=DC |last6=Fishman |first6=GI |last7=Amin |first7=KM |last8=Kaiser |first8=LR |last9=Albelda |first9=SM}}</ref><ref>{{cite journal | pmid = 8700844 | pmc=39867 | volume=93 | issue=5 | title=Bystander killing of cancer cells by herpes simplex virus thymidine kinase gene is mediated by connexins | year=1996 | month=March | pages=1831–5 | bibcode = 1996PNAS...93.1831M | author1 = Mesnil | first1 = Marc | last2 = Piccoli | first2 = Colette | last3 = Tiraby | first3 = Gerard | last4 = Willecke | first4 = Klaus | last5 = Yamasaki | first5 = Hiroshi | journal = Proceedings of the National Academy of Sciences of the United States of America | doi = 10.1073/pnas.93.5.1831}}</ref><ref>{{cite journal | pmid =  8622159 | doi=10.3171/jns.1996.84.5.0839 | volume=84 | issue=5 | title=Protein and messenger RNA expression of connexin43 in astrocytomas: implications in brain tumor gene therapy | year=1996 | month=May | journal=J. Neurosurg. | pages=839–45; discussion 846 | last1 =  Shinoura | first1 =  Nobusada | last2 =  Chen | first2 =  Lin | last3 =  Wani | first3 =  Maqsood A. | last4 =  Kim | first4 =  Young Gyu | last5 =  Larson | first5 =  Jeffrey J. | last6 =  Warnick | first6 =  Ronald E. | last7 =  Simon | first7 =  Matthias | last8 =  Menon | first8 =  Anil G. | last9 =  Bi | first9 =  Wan Li}}</ref><ref>{{cite journal |pmid=8665496 | volume=56 | issue=12 | title=Herpes simplex virus thymidine kinase/ganciclovir-mediated apoptotic death of bystander cells | year=1996 | month=June | journal=Cancer Res. | pages=2697–702 |last1=Hamel |first1=W |last2=Magnelli |first2=L |last3=Chiarugi |first3=VP |last4=Israel |first4=MA}}</ref><ref>{{cite journal | pmid = 8986442 | volume=3 | issue=12 | title=Partial regression, yet incomplete eradication of mammary tumors in transgenic mice by retrovirally mediated HSVtk transfer 'in vivo' | year=1996 | month=December | journal=Gene Ther. | pages=1151–6 | last1 = Sacco | first1 = MG | last2 = Benedetti | first2 = S | last3 = Duflot-Dancer | first3 = A | last4 = Mesnil | first4 = M | last5 = Bagnasco | first5 = L | last6 = Strina | first6 = D | last7 = Fasolo | first7 = V | last8 = Villa | first8 = A | last9 = MacChi | first9 = P}}</ref><ref>{{cite journal | pmid = 12014914 | doi=10.1006/exer.2002.1155 | volume=74 | issue=3 | title=Cell death in retinitis pigmentosa: gap junctions and the 'bystander' effect | year=2002 | month=March | journal=Exp. Eye Res. | pages=327–36 | last1 = Ripps | first1 = Harris}}</ref> Later the bystander effect was also researched with regard to cells damaged by radiation or mechanical injury and therefore wound healing.<ref>{{cite journal | pmid = 12194273 | volume=99 | issue=1–4 | title=Bystander effects: intercellular transmission of radiation damage signals | year=2002 | journal=Radiat Prot Dosimetry | pages=159–62 | doi = 10.1093/oxfordjournals.rpd.a006751 | last1 = Little | first1 = JB | last2 = Azzam | first2 = EI | last3 = De Toledo | first3 = SM | last4 = Nagasawa | first4 = H}}</ref><ref>{{cite journal | pmid = 12194291 | volume=99 | issue=1–4 | title=Genotoxic damage in non-irradiated cells: contribution from the bystander effect | year=2002 | journal=Radiat Prot Dosimetry | pages=227–32 | doi = 10.1093/oxfordjournals.rpd.a006769 | last1 = Zhou | first1 = H | last2 = Randers-Pehrson | first2 = G | last3 = Suzuki | first3 = M | last4 = Waldren | first4 = CA | last5 = Hei | first5 = TK}}</ref><ref>{{cite journal | pmid = 12556327 | volume=79 | issue=1 | title=Radiation-induced genomic instability and bystander effects: related inflammatory-type responses to radiation-induced stress and injury? A review | year=2003 | month=January | journal=Int. J. Radiat. Biol. | pages=15–25 | last1 = Lorimore | first1 = SA | last2 = Wright | first2 = EG}}</ref><ref>{{cite journal | pmid = 14617290 | volume=11 | issue=6 | title=Role for gap junctional intercellular communications in wound repair | year=2003 | journal=Wound Repair Regen | pages=481–9 | doi = 10.1046/j.1524-475X.2003.11616.x | last1 = Ehrlich | first1 = HP | last2 = Diez | first2 = T}}</ref><ref>{{cite journal | pmid = 15927148 | doi=10.1016/j.bjps.2004.12.022 | volume=58 | issue=5 | title=Limiting burn extension by transient inhibition of Connexin43 expression at the site of injury | year=2005 | month=July | journal=Br J Plast Surg | pages=658–67 | last1 = Coutinho | first1 = P. | last2 = Qiu | first2 = C. | last3 = Frank | first3 = S. | last4 = Wang | first4 = C.M. | last5 = Brown | first5 = T. | last6 = Green | first6 = C.R. | last7 = Becker | first7 = D.L.}}</ref> Disease also seems to have an effect on the ability of gap junctions to fulfill their roles in wound healing.<ref>{{cite journal | pmid =  17717278 | doi=10.2337/db07-0613 | volume=56 | issue=11 | title=Abnormal connexin expression underlies delayed wound healing in diabetic skin | year=2007 | month=November | journal=Diabetes | pages=2809–17 | last1 =  Wang | first1 =  C. M. | last2 =  Lincoln | first2 =  J. | last3 =  Cook | first3 =  J. E. | last4 =  Becker | first4 =  D. L.}}</ref><ref>{{cite journal | pmid = 9550065 | volume=9 | issue=1 | title=Considerations for the aesthetic restoration of endodontically treated anterior teeth following intracoronal bleaching | year=1997 | journal=Pract Periodontics Aesthet Dent | pages=117–28 | last1 = Rivera | first1 = EM | last2 = Vargas | first2 = M | last3 = Ricks-Williamson | first3 = L}}</ref>
 ====Tissue restructuring====
-While there has been a tendency to focus on the bystander effect in disease due to the possibility of therapeutic avenues there is evidence that there is a more central role in normal development of tissues. Death of some cells and their surrounding matrix may be required for a tissue to reach its final configuration and gap junctions also appear essential to this process.<ref>{{cite journal | pmid = 12878681 | volume=23 | issue=16 | title=Gap junctions mediate bystander cell death in developing retina | year=2003 | month=July | journal=J. Neurosci. | pages=6413–22}}</ref><ref>{{cite journal | pmid =  15225205 | doi=10.1111/j.1067-1927.2004.012310.x | volume=12 | issue=3 | title=Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication | year=2004 | journal=Wound Repair Regen | pages=269–75}}</ref> There are also more complex studies that try and combine our understanding of the simultaneous roles of gap junctions in both wound healing and tissue development.<ref>{{cite journal | pmid = 16628254 | doi=10.1172/JCI27186 | pmc=1440704 | volume=116 | issue=5 | title=Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response | year=2006 | month=May | journal=J. Clin. Invest. | pages=1243–53}}</ref><ref>{{cite journal | pmid =  19966054 | doi=10.1152/ajpheart.00806.2009 | pmc=2822575 | volume=298 | issue=2 | title=Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling | year=2010 | month=February | journal=Am. J. Physiol. Heart Circ. Physiol. | pages=H477–87}}</ref>
+While there has been a tendency to focus on the bystander effect in disease due to the possibility of therapeutic avenues there is evidence that there is a more central role in normal development of tissues. Death of some cells and their surrounding matrix may be required for a tissue to reach its final configuration and gap junctions also appear essential to this process.<ref>{{cite journal | pmid = 12878681 | volume=23 | issue=16 | title=Gap junctions mediate bystander cell death in developing retina | year=2003 | month=July | journal=J. Neurosci. | pages=6413–22 | last1 = Cusato | first1 = K | last2 = Bosco | first2 = A | last3 = Rozental | first3 = R | last4 = Guimarães | first4 = CA | last5 = Reese | first5 = BE | last6 = Linden | first6 = R | last7 = Spray | first7 = DC}}</ref><ref>{{cite journal | pmid =  15225205 | doi=10.1111/j.1067-1927.2004.012310.x | volume=12 | issue=3 | title=Mast cells promote fibroblast populated collagen lattice contraction through gap junction intercellular communication | year=2004 | journal=Wound Repair Regen | pages=269–75 | last1 =  Moyer | first1 =  Kurtis E. | last2 =  Saggers | first2 =  Gregory C. | last3 =  Ehrlich | first3 =  H. Paul}}</ref> There are also more complex studies that try and combine our understanding of the simultaneous roles of gap junctions in both wound healing and tissue development.<ref>{{cite journal | pmid = 16628254 | doi=10.1172/JCI27186 | pmc=1440704 | volume=116 | issue=5 | title=Connexin 26 regulates epidermal barrier and wound remodeling and promotes psoriasiform response | year=2006 | month=May | journal=J. Clin. Invest. | pages=1243–53 | last1 = Djalilian | first1 = A. R. | last2 = McGaughey | first2 = D | last3 = Patel | first3 = S | last4 = Seo | first4 = EY | last5 = Yang | first5 = C | last6 = Cheng | first6 = J | last7 = Tomic | first7 = M | last8 = Sinha | first8 = S | last9 = Ishida-Yamamoto | first9 = A}}</ref><ref>{{cite journal | pmid =  19966054 | doi=10.1152/ajpheart.00806.2009 | pmc=2822575 | volume=298 | issue=2 | title=Reduced expression of Cx43 attenuates ventricular remodeling after myocardial infarction via impaired TGF-beta signaling | year=2010 | month=February | journal=Am. J. Physiol. Heart Circ. Physiol. | pages=H477–87 | last1 =  Zhang | first1 =  Y. | last2 =  Wang | first2 =  H. | last3 =  Kovacs | first3 =  A. | last4 =  Kanter | first4 =  E. M. | last5 =  Yamada | first5 =  K. A.}}</ref>
 ===Areas of electrical coupling===
@@ Line 78: / Line 78: @@
 ====Neurons====
-A gap junction located in neurons is often referred to as an [[electrical synapse]]. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. Few locations have been discovered where there is significant coupling between [[neuron]]s in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the [[vestibular nucleus]], the nucleus of [[trigeminal nerve]], the [[inferior olivary nucleus]], and the [[ventral tegmentum|Ventral Tegmental Area]]. There has been some observation of weak neuron to [[glial cell]] coupling in the [[locus coeruleus]], and in the [[cerebellum]] between [[Purkinje neuron]]s and [[Astrocyte#Bergmann glia|Bergmann glial cell]]s. It appears that [[astrocyte]]s are coupled by gap junctions, both to other astrocytes and to [[oligodendrocyte]]s.<ref>{{cite journal|last=Orthmann-Murphy|first=Jennifer L.|coauthors=Abrams, Charles K.; Scherer, Steven S.|title=Gap Junctions Couple Astrocytes and Oligodendrocytes|journal=Journal of Molecular Neuroscience|date=May 2008|volume=35|issue=1|pages=101–116|doi=10.1007/s12031-007-9027-5|accessdate=18 June 2012|pmid=18236012|pmc=2650399}}</ref>  Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in [[Pelizaeus-Merzbacher disease]] and [[multiple sclerosis]].
+A gap junction located in neurons is often referred to as an [[electrical synapse]]. The electrical synapse was discovered using electrical measurements before the gap junction structure was described. Few locations have been discovered where there is significant coupling between [[neuron]]s in the brain. Structures in the brain that have been shown to contain electrically coupled neurons include the [[vestibular nucleus]], the nucleus of [[trigeminal nerve]], the [[inferior olivary nucleus]], and the [[ventral tegmentum|Ventral Tegmental Area]]. There has been some observation of weak neuron to [[glial cell]] coupling in the [[locus coeruleus]], and in the [[cerebellum]] between [[Purkinje neuron]]s and [[Astrocyte#Bergmann glia|Bergmann glial cell]]s. It appears that [[astrocyte]]s are coupled by gap junctions, both to other astrocytes and to [[oligodendrocyte]]s.<ref>{{cite journal|last=Orthmann-Murphy|first=Jennifer L.|coauthors=Abrams, Charles K.; Scherer, Steven S.|title=Gap Junctions Couple Astrocytes and Oligodendrocytes|journal=Journal of Molecular Neuroscience|date=May 2008|volume=35|issue=1|pages=101–116|doi=10.1007/s12031-007-9027-5|pmid=18236012|pmc=2650399}}</ref>  Moreover, mutations in the gap junction genes Cx43 and Cx56.6 cause white matter degeneration similar to that observed in [[Pelizaeus-Merzbacher disease]] and [[multiple sclerosis]].
 Connexin proteins expressed in neuronal gap junctions include:
@@ Line 93: / Line 93: @@
 ===Where did the name come from?===
-Gap junctions were so named because of the "gap" shown to be present at these special junctions between two cells.<ref>{{Cite journal|pmid=2107199 |pmc=2107199 |year=1967 |first1=J. P. |last1=Revel |first2=M. J. |last2=Karnovsky |title=HEXAGONAL ARRAY OF SUBUNITS IN INTERCELLULAR JUNCTIONS OF THE MOUSE HEART AND LIVER |volume=33 |issue=3 |pages=C7–C12 |journal=The Journal of Cell Biology |doi=10.1083/jcb.33.3.C7}}</ref> With the increased resolution of the [[transmission electron microscope]] (TEM) gap junction structures were first able to be seen and described in around 1953.[[File:Annular Gap Junction Vesicle.jpg|Annular Gap Junction Vesicle|right|thumbnail| Annular gap junction cross section in TEM thin section. Gap junctions are usually linear rather than annular in TEM thin sections. It is thought that annular gap junctions result from engulfment by one of the two cells of the membrane plaque to form a vesicle within the cell. This example shows three layers to the junction structure. The membrane from each cell is the dark line with the whiter narrow gap between the two darkly stained membranes. In such electron micrographs there may appear to be up to 7 layers. Two lipid mono-layers in each membrane can stain as 3 layers plus one layer from the gap between them, similar to two stacked bread sandwiches with space between them]] The term "gap junction" appeared to be coined about 16 years later circa 1969.<ref>{{cite journal | pmid = 5765759 | pmc=2107650 | volume=40 | issue=3 | title=Junctions between intimately apposed cell membranes in the vertebrate brain | year=1969 | month=March | journal=J. Cell Biol. | pages=648–77}}</ref><ref>DEMONSTRATION OF "GAP JUNCTIONS" BETWEEN SMOOTH MUSCLE CELLS Yasuo Uehara, Geoffrey Burnstock. J Cell Biol. 1970 January 1; 44(1)  215–217.PMCID: PMC2107775</ref><ref>{{cite journal | pmid = 4105112 | pmc=2107902 | volume=45 | issue=2 | title=A fine structural analysis of intercellular junctions in the mouse liver | year=1970 | month=May | journal=J. Cell Biol. | pages=272–90}}</ref> A similar narrow regular gap was not demonstrated in other [[intercellular junctions]] photographed using the TEM at the time.
+Gap junctions were so named because of the "gap" shown to be present at these special junctions between two cells.<ref>{{Cite journal|pmid=2107199 |pmc=2107199 |year=1967 |first1=J. P. |last1=Revel |first2=M. J. |last2=Karnovsky |title=HEXAGONAL ARRAY OF SUBUNITS IN INTERCELLULAR JUNCTIONS OF THE MOUSE HEART AND LIVER |volume=33 |issue=3 |pages=C7–C12 |journal=The Journal of Cell Biology |doi=10.1083/jcb.33.3.C7|last3=Aitchison|first3=EJ|last4=Smith|first4=EG|last5=Farrell|first5=ID|last6=Gutschik|first6=E}}</ref> With the increased resolution of the [[transmission electron microscope]] (TEM) gap junction structures were first able to be seen and described in around 1953.[[File:Annular Gap Junction Vesicle.jpg|Annular Gap Junction Vesicle|right|thumbnail| Annular gap junction cross section in TEM thin section. Gap junctions are usually linear rather than annular in TEM thin sections. It is thought that annular gap junctions result from engulfment by one of the two cells of the membrane plaque to form a vesicle within the cell. This example shows three layers to the junction structure. The membrane from each cell is the dark line with the whiter narrow gap between the two darkly stained membranes. In such electron micrographs there may appear to be up to 7 layers. Two lipid mono-layers in each membrane can stain as 3 layers plus one layer from the gap between them, similar to two stacked bread sandwiches with space between them]] The term "gap junction" appeared to be coined about 16 years later circa 1969.<ref>{{cite journal | pmid = 5765759 | pmc=2107650 | volume=40 | issue=3 | title=Junctions between intimately apposed cell membranes in the vertebrate brain | year=1969 | month=March | journal=J. Cell Biol. | pages=648–77 | doi = 10.1083/jcb.40.3.648 | last1 = Brightman | first1 = MW | last2 = Reese | first2 = TS}}</ref><ref>DEMONSTRATION OF "GAP JUNCTIONS" BETWEEN SMOOTH MUSCLE CELLS Yasuo Uehara, Geoffrey Burnstock. J Cell Biol. 1970 January 1; 44(1)  215–217.PMCID: PMC2107775</ref><ref>{{cite journal | pmid = 4105112 | pmc=2107902 | volume=45 | issue=2 | title=A fine structural analysis of intercellular junctions in the mouse liver | year=1970 | month=May | journal=J. Cell Biol. | pages=272–90 | doi = 10.1083/jcb.45.2.272 | last1 = Goodenough | first1 = DA | last2 = Revel | first2 = JP}}</ref> A similar narrow regular gap was not demonstrated in other [[intercellular junctions]] photographed using the TEM at the time.
 ===Form and indicator of function===
-Well before the demonstration of the "gap" in gap junctions they were seen at the junction of neighboring nerve cells. The close proximity of the neighboring cell membranes at the gap junction lead researchers to speculate that they had a role in intercellular communication, in particular the transmission of electrical signals.<ref>{{Cite journal|pmid=13037850 |year=1953 |first1=J. D. |last1=Robertson |title=Ultrastructure of two invertebrate synapses |volume=82 |issue=2 |pages=219–23 |journal=Proceedings of the Society for Experimental Biology and Medicine}}</ref><ref>{{Cite book|editor1-first=Michael |editor1-last=Locke |year=1963 |title=Cellular membranes in development |publisher=Academic Press |location=New York |oclc=261587041 |last1=Robertson |first1=J. D. |chapter= |pages=}}{{Page needed|date=September 2010}}</ref><ref>{{Cite journal|pmid=7033238 |pmc=2112820 |title=Membrane structure |journal=The Journal of Cell Biology |year=1981 |volume=91 |issue=3 |author=Robertson |pages=189s–204s |doi=10.1083/jcb.91.3.189s |jstor=1609517}}</ref> Gap junctions were also proven to be electrically rectifying and referred to as an [[electrical synapse]].<ref>{{Cite journal|doi=10.1038/180342a0 |title=Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse |year=1957 |last1=Furshpan |first1=E. J. |first2=D. D. |journal=Nature |volume=180 |pages=342–3 |pmid=13464833 |issue=4581 |last2=Potter}}</ref><ref>{{Cite journal|pmid=13642302 |pmc=1356828 |url=http://jp.physoc.org/content/145/2/289.full.pdf+html |year=1959 |author1=Furshpan |first2=DD |title=Transmission at the giant motor synapses of the crayfish |volume=145 |issue=2 |pages=289–325 |journal=The Journal of physiology |last2=Potter}}</ref> Later it was found that chemicals could also be transported between cells through gap junctions.<ref>{{cite journal | pmid = 5360587 | volume=166 | issue=3913 | title=Permeability and structure of junctional membranes at an electrotonic synapse | year=1969 | month=December | journal=Science | pages=1641–3 | doi=10.1126/science.166.3913.1641}}</ref> Implicit or explicit in most of the early studies is that the area of the gap junction was different in structure to the surrounding membranes in a way that made it look different. The gap junction had been shown to create a micro-environment between the two cells in the extra-cellular space or "gap". This portion of extra-cellular space was somewhat isolated from the surrounding space and also bridged by what we now call connexon pairs which form even more tightly sealed bridges that cross the gap junction gap between two cells. When viewed in the plane of the membrane by freeze fracture techniques higher resolution distribution of connexons within the gap junction plaque is possible.<ref>{{cite journal | pmid = 4935338 | doi=10.1083/jcb.47.1.49 | pmc=2108397 | volume=47 | issue=1 | title=An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture | year=1970 | month=October | journal=J. Cell Biol. | pages=49–60}}</ref> Connexin free islands are observed in some junctions. The observation was largely without explanation until vesicles were shown by Peracchia using TEM thin sections to be systematically associated with gap junction plaques.<ref>{{cite journal | pmid = 4120610 | pmc=2108965 | volume=57 | issue=1 | title=Low resistance junctions in crayfish. II. Structural details and further evidence for intercellular channels by freeze-fracture and negative staining | year=1973 | month=April | journal=J. Cell Biol. | pages=54–65}}</ref> Peracchia's study was probably also the first study to describe paired connexon structures which he called somewhat simply a "globule". Studies showing vesicles associated with gap junctions and proposing the vesicle contents may move across the junction plaques between two cells were rare as most studies focused on the connexons rather than vesicles. A later study using a combination of microscopy techniques confirmed the early evidence of a probable function for gap junctions in intercellular vesicle transfer. Areas of vesicle transfer were associated with connexin free islands within gap junction plaques.<ref>{{cite journal |pmid=12972275 | doi=10.1016/S1065-6995(03)00140-9 | volume=27 | issue=9 | title=Are gap junction membrane plaques implicated in intercellular vesicle transfer? | year=2003 | journal=Cell Biol. Int. | pages=711–7}}</ref>
+Well before the demonstration of the "gap" in gap junctions they were seen at the junction of neighboring nerve cells. The close proximity of the neighboring cell membranes at the gap junction lead researchers to speculate that they had a role in intercellular communication, in particular the transmission of electrical signals.<ref>{{Cite journal|pmid=13037850 |year=1953 |first1=J. D. |last1=Robertson |title=Ultrastructure of two invertebrate synapses |volume=82 |issue=2 |pages=219–23 |journal=Proceedings of the Society for Experimental Biology and Medicine}}</ref><ref>{{Cite book|editor1-first=Michael |editor1-last=Locke |year=1963 |title=Cellular membranes in development |publisher=Academic Press |location=New York |oclc=261587041 |last1=Robertson |first1=J. D. |chapter= |pages=}}{{Page needed|date=September 2010}}</ref><ref>{{Cite journal|pmid=7033238 |pmc=2112820 |title=Membrane structure |journal=The Journal of Cell Biology |year=1981 |volume=91 |issue=3 |author=Robertson |pages=189s–204s |doi=10.1083/jcb.91.3.189s |jstor=1609517}}</ref> Gap junctions were also proven to be electrically rectifying and referred to as an [[electrical synapse]].<ref>{{Cite journal|doi=10.1038/180342a0 |title=Mechanism of Nerve-Impulse Transmission at a Crayfish Synapse |year=1957 |last1=Furshpan |first1=E. J. |first2=D. D. |journal=Nature |volume=180 |pages=342–3 |pmid=13464833 |issue=4581 |last2=Potter}}</ref><ref>{{Cite journal|pmid=13642302 |pmc=1356828 |url=http://jp.physoc.org/content/145/2/289.full.pdf+html |year=1959 |author1=Furshpan |first2=DD |title=Transmission at the giant motor synapses of the crayfish |volume=145 |issue=2 |pages=289–325 |journal=The Journal of physiology |last2=Potter}}</ref> Later it was found that chemicals could also be transported between cells through gap junctions.<ref>{{cite journal | pmid = 5360587 | volume=166 | issue=3913 | title=Permeability and structure of junctional membranes at an electrotonic synapse | year=1969 | month=December | journal=Science | pages=1641–3 | doi=10.1126/science.166.3913.1641 | last1 = Payton | first1 = B. W. | last2 = Bennett | first2 = M. V. L. | last3 = Pappas | first3 = G. D.}}</ref> Implicit or explicit in most of the early studies is that the area of the gap junction was different in structure to the surrounding membranes in a way that made it look different. The gap junction had been shown to create a micro-environment between the two cells in the extra-cellular space or "gap". This portion of extra-cellular space was somewhat isolated from the surrounding space and also bridged by what we now call connexon pairs which form even more tightly sealed bridges that cross the gap junction gap between two cells. When viewed in the plane of the membrane by freeze fracture techniques higher resolution distribution of connexons within the gap junction plaque is possible.<ref>{{cite journal | pmid = 4935338 | doi=10.1083/jcb.47.1.49 | pmc=2108397 | volume=47 | issue=1 | title=An interpretation of liver cell membrane and junction structure based on observation of freeze-fracture replicas of both sides of the fracture | year=1970 | month=October | journal=J. Cell Biol. | pages=49–60 | last1 = Chalcroft | first1 = J. P. | last2 = Bullivant | first2 = S}}</ref> Connexin free islands are observed in some junctions. The observation was largely without explanation until vesicles were shown by Peracchia using TEM thin sections to be systematically associated with gap junction plaques.<ref>{{cite journal | pmid = 4120610 | pmc=2108965 | volume=57 | issue=1 | title=Low resistance junctions in crayfish. II. Structural details and further evidence for intercellular channels by freeze-fracture and negative staining | year=1973 | month=April | journal=J. Cell Biol. | pages=54–65 | last1 = Peracchia | first1 = C}}</ref> Peracchia's study was probably also the first study to describe paired connexon structures which he called somewhat simply a "globule". Studies showing vesicles associated with gap junctions and proposing the vesicle contents may move across the junction plaques between two cells were rare as most studies focused on the connexons rather than vesicles. A later study using a combination of microscopy techniques confirmed the early evidence of a probable function for gap junctions in intercellular vesicle transfer. Areas of vesicle transfer were associated with connexin free islands within gap junction plaques.<ref>{{cite journal |pmid=12972275 | doi=10.1016/S1065-6995(03)00140-9 | volume=27 | issue=9 | title=Are gap junction membrane plaques implicated in intercellular vesicle transfer? | year=2003 | journal=Cell Biol. Int. | pages=711–7 |last1=Gruijters |first1=W}}</ref>
 ===Gap junctions and the electrical and chemical nerve synapses===
@@ Line 110: / Line 110: @@
 ====The "plaque" or "formation plaque"====
-Early descriptions of "gap junctions" and "connexons" did not refer to them as such and many other terms were used. It is likely that "synaptic disks" <ref>{{cite journal | pmid = 14069795 | pmc=2106854 | volume=19 | title=THE OCCURRENCE OF A SUBUNIT PATTERN IN THE UNIT MEMBRANES OF CLUB ENDINGS IN MAUTHNER CELL SYNAPSES IN GOLDFISH BRAINS | year=1963 | month=October | journal=J. Cell Biol. | pages=201–21}}</ref> were an accurate reference to gap junction plaques. While the detailed structure and function of the connexon was described in a limited way at the time the gross "disk" structure was relatively large and easily seen by various TEM techniques. Disks allowed researchers using TEM to easily locate the connexons contained within the disk like patches in vivo and in vitro. The disk or "plaque" appeared to have structural properties different to those imparted by the connexons alone.<ref>{{cite journal | pmid = 4109925 | pmc=2108629 | volume=52 | issue=2 | title=The structural organization of the septate and gap junctions of Hydra | year=1972 | month=February | journal=J. Cell Biol. | pages=397–408}}</ref> It was thought that if the area of membrane in the plaque transmitted signals the area of membrane would have to be sealed in some way to prevent leakage.<ref>STUDIES ON AN EPITHELIAL (GLAND) CELL JUNCTION : I. Modifications of Surface Membrane Permeability Werner R. Loewenstein, Yoshinobu Kanno J Cell Biol. 1964 September 1; 22(3)  565–586. PMCID</ref>
+Early descriptions of "gap junctions" and "connexons" did not refer to them as such and many other terms were used. It is likely that "synaptic disks" <ref>{{cite journal | pmid = 14069795 | pmc=2106854 | volume=19 | title=THE OCCURRENCE OF A SUBUNIT PATTERN IN THE UNIT MEMBRANES OF CLUB ENDINGS IN MAUTHNER CELL SYNAPSES IN GOLDFISH BRAINS | year=1963 | month=October | journal=J. Cell Biol. | pages=201–21 | doi = 10.1083/jcb.19.1.201 | last1 = Robertson | first1 = JD | issue = 1}}</ref> were an accurate reference to gap junction plaques. While the detailed structure and function of the connexon was described in a limited way at the time the gross "disk" structure was relatively large and easily seen by various TEM techniques. Disks allowed researchers using TEM to easily locate the connexons contained within the disk like patches in vivo and in vitro. The disk or "plaque" appeared to have structural properties different to those imparted by the connexons alone.<ref>{{cite journal | pmid = 4109925 | pmc=2108629 | volume=52 | issue=2 | title=The structural organization of the septate and gap junctions of Hydra | year=1972 | month=February | journal=J. Cell Biol. | pages=397–408 | doi = 10.1083/jcb.52.2.397 | last1 = Hand | first1 = AR | last2 = Gobel | first2 = S}}</ref> It was thought that if the area of membrane in the plaque transmitted signals the area of membrane would have to be sealed in some way to prevent leakage.<ref>STUDIES ON AN EPITHELIAL (GLAND) CELL JUNCTION : I. Modifications of Surface Membrane Permeability Werner R. Loewenstein, Yoshinobu Kanno J Cell Biol. 1964 September 1; 22(3)  565–586. PMCID</ref>
 Later studies showed gap junction plaques are home to non-connexin proteins making the modern usage of the terms "gap junction" and "gap junction plaque" non-interchangeable as the area of the gap junction plaque may contain proteins other than connexins.<ref name="Gruijters, WTM 1989 509–13"/><ref>{{Cite journal|doi=10.1016/S1065-6995(03)00140-9 |title=Are gap junction membrane plaques implicated in intercellular vesicle transfer? |year=2003 |last1=Gruijters |first1=WTM |journal=Cell Biology International |volume=27 |pages=711–7 |pmid=12972275 |issue=9}}</ref> Just as connexins do not always occupy the entire area of the plaque the other components described in the literature may be only long term or short term residents.<ref>Ozato-Sakurai N, Fujita A, Fujimoto T. "The distribution of phosphatidylinositol 4,5-bisphosphate in acinar cells of rat pancreas revealed with the freeze-fracture replica labeling method. ''PLoS One.'' 2011;6(8) e23567. Epub 2011 Aug 15. </ref>
-Studies allowing views inside the plane of the membrane of gap junctions during formation indicated that a "formation plaque" formed between two cells prior to the connexins moving in. They were particle free areas when observed by TEM FF indicating very small or no [[transmembrane protein]]s were likely present. Little is known about what structures make up the formation plaque or how the formation plaque's structure changes when connexins and other components move in or out. One of the earlier studies of the formation of small gap junctions describes rows of particles and particle free halos.<ref>{{cite journal | pmid = 4135001 | pmc=2109180 | volume=62 | issue=1 | title=Assembly of gap junctions during amphibian neurulation | year=1974 | month=July | journal=J. Cell Biol. | pages=32–47}}</ref> With larger gap junctions they were described as formation plaques with connexins moving into them. The particulate gap junctions were thought to form 4–6 hours after the formation plaques appeared.<ref>{{cite journal | pmid = 1083855 | pmc=2109697 | volume=69 | issue=3 | title=Hormonal regulation of gap junction differentiation | year=1976 | month=June | journal=J. Cell Biol. | pages=669–85}}</ref> How the connexins may be transported to the plaques using [[tubulin]] is becoming clearer.<ref name="ReferenceB"/><ref>Proc Natl Acad Sci U S A. 2002 Aug 6;99(16) 10446-51. Epub 2002 Jul 29. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM.</ref> [[File:Connexin43-Modulates-Cell-Polarity-and-Directional-Cell-Migration-by-Regulating-Microtubule-Dynamics-pone.0026379.s004.ogv|right|thumb|[[Immunofluorescence]] microscopy video of connexins being moved along microtubles to the surface of a cell.<ref>PLoS One. 2011;6(10) e26379. Epub 2011 Oct 14.
+Studies allowing views inside the plane of the membrane of gap junctions during formation indicated that a "formation plaque" formed between two cells prior to the connexins moving in. They were particle free areas when observed by TEM FF indicating very small or no [[transmembrane protein]]s were likely present. Little is known about what structures make up the formation plaque or how the formation plaque's structure changes when connexins and other components move in or out. One of the earlier studies of the formation of small gap junctions describes rows of particles and particle free halos.<ref>{{cite journal | pmid = 4135001 | pmc=2109180 | volume=62 | issue=1 | title=Assembly of gap junctions during amphibian neurulation | year=1974 | month=July | journal=J. Cell Biol. | pages=32–47 | doi = 10.1083/jcb.62.1.32 | last1 = Decker | first1 = RS | last2 = Friend | first2 = DS}}</ref> With larger gap junctions they were described as formation plaques with connexins moving into them. The particulate gap junctions were thought to form 4–6 hours after the formation plaques appeared.<ref>{{cite journal | pmid = 1083855 | pmc=2109697 | volume=69 | issue=3 | title=Hormonal regulation of gap junction differentiation | year=1976 | month=June | journal=J. Cell Biol. | pages=669–85 | doi = 10.1083/jcb.69.3.669 | last1 = Decker | first1 = RS}}</ref> How the connexins may be transported to the plaques using [[tubulin]] is becoming clearer.<ref name="ReferenceB"/><ref>Proc Natl Acad Sci U S A. 2002 Aug 6;99(16) 10446-51. Epub 2002 Jul 29. Dynamic trafficking and delivery of connexons to the plasma membrane and accretion to gap junctions in living cells. Lauf U, Giepmans BN, Lopez P, Braconnot S, Chen SC, Falk MM.</ref> [[File:Connexin43-Modulates-Cell-Polarity-and-Directional-Cell-Migration-by-Regulating-Microtubule-Dynamics-pone.0026379.s004.ogv|right|thumb|[[Immunofluorescence]] microscopy video of connexins being moved along microtubles to the surface of a cell.<ref>PLoS One. 2011;6(10) e26379. Epub 2011 Oct 14.
-Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics. Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C. Source Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.</ref>]]  The formation plaque and non-connexin part of the classical gap junction plaque have been difficult for early researchers to analyse. It appears in TEM FF and thin section to be a lipid membrane domain that can somehow form a comparatively rigid barrier to other lipids and proteins. There has been indirect evidence for certain lipids being preferentially involved with the formation plaque but this cannot be considered definitive.<ref>{{cite journal | pmid = 1698798 | volume=96 | title=Increased gap junction assembly between cultured cells upon cholesterol supplementation | year=1990 | month=June | journal=J. Cell. Sci. | pages=231–8 | issue=2}}</ref><ref>{{cite journal | pmid =  22049024 | doi=10.1091/mbc.E11-02-0141 | volume=23 | issue=1 | title=Gap junction assembly: roles for the formation plaque and regulation by the C-terminus of connexin43 | pmc=3248906 | year=2012 | month=January | journal=Mol. Biol. Cell | pages=71–86}}</ref> It is difficult to envisage breaking up the membrane to analyse membrane plaques without affecting their composition. By study of connexins still in membranes lipids associated with the connexins have been studied.<ref>{{cite journal | pmid = 19686581 | doi=10.1186/1741-7007-7-52 | volume=7 | title=Connexin channels and phospholipids: association and modulation | pmc=2733891 | year=2009 | journal=BMC Biol. | pages=52}}</ref> It was found that specific connexins tended to associate preferentially with specific phospholipids. As formation plaques precede connexins these results still give no certainty as to what is unique about the composition of plaques themselves. Other findings show connexins associate with protein scaffolds used in another junction, the zonula occludens ZO1.<ref name="Naomi Kamasawa PMC">Connexin45-containing neuronal gap junctions in rodent retina also contain connexin36 in both apposing hemiplaques, forming bi-homotypic gap junctions, with scaffolding contributed by zonula occludens-1 Xinbo Li, Naomi Kamasawa, Cristina Ciolofan, Carl O. Olson, Shijun Lu, Kimberly G.V. Davidson, Thomas Yasumura, Ryuichi Shigemoto, John E. Rash, James I. Nagy J Neurosci. Author manuscript; available in PMC 2009 March 24.Published in final edited form as: ''J Neurosci.'' 2008 September 24; 28(39)  9769–9789. doi: 10.1523/JNEUROSCI.2137-08.2008
+Connexin43 modulates cell polarity and directional cell migration by regulating microtubule dynamics. Francis R, Xu X, Park H, Wei CJ, Chang S, Chatterjee B, Lo C. Source Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.</ref>]]  The formation plaque and non-connexin part of the classical gap junction plaque have been difficult for early researchers to analyse. It appears in TEM FF and thin section to be a lipid membrane domain that can somehow form a comparatively rigid barrier to other lipids and proteins. There has been indirect evidence for certain lipids being preferentially involved with the formation plaque but this cannot be considered definitive.<ref>{{cite journal | pmid = 1698798 | volume=96 | title=Increased gap junction assembly between cultured cells upon cholesterol supplementation | year=1990 | month=June | journal=J. Cell. Sci. | pages=231–8 | issue=2 | last1 = Meyer | first1 = R | last2 = Malewicz | first2 = B | last3 = Baumann | first3 = WJ | last4 = Johnson | first4 = RG}}</ref><ref>{{cite journal | pmid =  22049024 | doi=10.1091/mbc.E11-02-0141 | volume=23 | issue=1 | title=Gap junction assembly: roles for the formation plaque and regulation by the C-terminus of connexin43 | pmc=3248906 | year=2012 | month=January | journal=Mol. Biol. Cell | pages=71–86 | last1 =  Johnson | first1 =  R. G. | last2 =  Reynhout | first2 =  J. K. | last3 =  Tenbroek | first3 =  E. M. | last4 =  Quade | first4 =  B. J. | last5 =  Yasumura | first5 =  T. | last6 =  Davidson | first6 =  K. G. V. | last7 =  Sheridan | first7 =  J. D. | last8 =  Rash | first8 =  J. E.}}</ref> It is difficult to envisage breaking up the membrane to analyse membrane plaques without affecting their composition. By study of connexins still in membranes lipids associated with the connexins have been studied.<ref>{{cite journal | pmid = 19686581 | doi=10.1186/1741-7007-7-52 | volume=7 | title=Connexin channels and phospholipids: association and modulation | pmc=2733891 | year=2009 | journal=BMC Biol. | pages=52 | last1 = Locke | first1 = Darren | last2 = Harris | first2 = Andrew L}}</ref> It was found that specific connexins tended to associate preferentially with specific phospholipids. As formation plaques precede connexins these results still give no certainty as to what is unique about the composition of plaques themselves. Other findings show connexins associate with protein scaffolds used in another junction, the zonula occludens ZO1.<ref name="Naomi Kamasawa PMC">Connexin45-containing neuronal gap junctions in rodent retina also contain connexin36 in both apposing hemiplaques, forming bi-homotypic gap junctions, with scaffolding contributed by zonula occludens-1 Xinbo Li, Naomi Kamasawa, Cristina Ciolofan, Carl O. Olson, Shijun Lu, Kimberly G.V. Davidson, Thomas Yasumura, Ryuichi Shigemoto, John E. Rash, James I. Nagy J Neurosci. Author manuscript; available in PMC 2009 March 24.Published in final edited form as: ''J Neurosci.'' 2008 September 24; 28(39)  9769–9789. doi: 10.1523/JNEUROSCI.2137-08.2008
 PMCID: PMC2638127</ref> While this helps us understand how connexins may be moved into a gap junction formation plaque the composition of the plaque itself is still somewhat sketchy. Some headway on the in vivo composition of the gap junction plaque is being made using TEM FRIL.<ref name="Naomi Kamasawa PMC"/><ref>The Distribution of Phosphatidylinositol 4,5-Bisphosphate in Acinar Cells of Rat Pancreas Revealed with the Freeze-Fracture Replica Labeling Method Nami Ozato-Sakurai, Akikazu Fujita, Toyoshi Fujimoto PLoS One. 2011; 6(8)  e23567. Published online 2011 August 15. doi: 10.1371/journal.pone.0023567 PMCID: PMC3156236</ref>

v t e Proteins of epithelium
Lateral/cell–cell	Cell adhesion molecules: Adherens junction Cadherin Desmosome Desmoglein Ion channels: Gap junction/Connexon Connexin Cytoskeleton: Desmosome Desmoplakin Plakoglobin Tonofibril other membrane proteins: Tight junction Claudin Occludin MARVELD2
Basal/cell–matrix	Basal lamina Hemidesmosome/Tonofibril Focal adhesion Costamere
Apical	Cilia/Kinocilium Microvilli/Stereocilia (STRC)