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GJB6

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GJB6
Identifiers
AliasesGJB6, CX30, DFNA3, DFNA3B, DFNB1B, ECTD2, ED2, EDH, HED, HED2, gap junction protein beta 6
External IDsOMIM: 604418; MGI: 107588; HomoloGene: 4936; GeneCards: GJB6; OMA:GJB6 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10804

14623

Ensembl

ENSG00000121742

ENSMUSG00000040055

UniProt

O95452

P70689

RefSeq (mRNA)

NM_001010937
NM_001271663
NM_008128

RefSeq (protein)

NP_001010937
NP_001258592

Location (UCSC)Chr 13: 20.22 – 20.23 MbChr 14: 57.36 – 57.37 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gap junction beta-6 protein (GJB6), also known as connexin 30 (Cx30) — is a protein that in humans is encoded by the GJB6 gene.[5][6][7] Connexin 30 (Cx30) is one of several gap junction proteins expressed in the inner ear.[8] Mutations in gap junction genes have been found to lead to both syndromic and nonsyndromic deafness.[9] Mutations in this gene are associated with Clouston syndrome (i.e., hydrotic ectodermal dysplasia).

Function

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The connexin gene family codes for the protein subunits of gap junction channels that mediate direct diffusion of ions and metabolites between the cytoplasm of adjacent cells. Connexins span the plasma membrane 4 times, with amino- and carboxy-terminal regions facing the cytoplasm. Connexin genes are expressed in a cell type-specific manner with overlapping specificity. The gap junction channels have unique properties depending on the type of connexins constituting the channel.[supplied by OMIM][7]

Connexin 30 is prevalent in the two distinct gap junction systems found in the cochlea: the epithelial cell gap junction network, which couple non-sensory epithelial cells, and the connective tissue gap junction network, which couple connective tissue cells. Gap junctions serve the important purpose of recycling potassium ions that pass through hair cells during mechanotransduction back to the endolymph.[10]

Connexin 30 has been found to be co-localized with connexin 26.[11] Cx30 and Cx26 have also been found to form heteromeric and heterotypic channels. The biochemical properties and channel permeabilities of these more complex channels differ from homotypic Cx30 or Cx26 channels.[12] Overexpression of Cx30 in Cx30 null mice restored Cx26 expression and normal gap junction channel functioning and calcium signaling, but it is described that Cx26 expression is altered in Cx30 null mice. The researchers hypothesized that co-regulation of Cx26 and Cx30 is dependent on phospholipase C signaling and the NF-κB pathway.[13]

The cochlea contains two cell types, auditory hair cells for mechanotransduction and supporting cells. Gap junction channels are only found between cochlear supporting cells.[14] While gap junctions in the inner ear are critically involved in potassium recycling to the endolymph, connexin expression in the supporting cells surrounding the organ of Corti have been found to support epithelial tissue lesion repair following loss of sensory hair cells. An experiment with Cx30 null mice found deficits in lesion closure and repair of the organ of Corti following hair cell loss, suggesting that Cx30 has a role in regulating lesion repair response.[15]

Astrocytes play a crucial role in synaptic physiology and information processing in the brain. A key characteristic of astrocytes is their expression of Cx30, which influences cognitive processes by shaping synaptic and network activities. This Cx-mediated astroglial network regulates the efficiency of extracellular potassium (K+) and glutamate clearance at synapses,[16] as well as the long-distance trafficking of energy metabolites to fuel active synapses.[17][18] However, Cxs do not only form gap junction channels with other astrocytes; they can also mediate direct exchange with the extracellular space when forming hemichannels.[19]

Cx30 protein levels set the size of astrocytic networks, and can be modulated by neuronal activity, indicating a close relationship between astrocytic network size and the activation of underlying neuronal networks. However, this modulation is complex, as it differentially impacts principal cells and interneurons.[20] Additionally, Cx30 can also act via other mechanisms, such as signaling and protein interactions. Recent research has shown that the increase in Cx30 levels between P10 to P50 controls the closure of the critical period in the mouse visual cortex through a signaling pathway that regulates the extracellular matrix and interneuron maturation.[21]

In the hippocampus, decreased Cx30 expression reduces the size of astroglial networks, while upregulation of Cx30 increases their size.[22] In both cases, it decreases spontaneous and evoked synaptic transmission. This effect results from reduced neuronal excitability, leading to alterations in the induction of synaptic plasticity and impairments in learning processes in vivo. Altogether, this suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.

Clinical significance

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Auditory

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Connexin 26 and connexin 30 are commonly accepted to be the predominant gap junction proteins in the cochlea. Genetic knockout experiments in mice has shown that knockout of either Cx26 or Cx30 produces deafness.[23][24] However, recent research suggests that Cx30 knockout produces deafness due to subsequent downregulation of Cx26, and one mouse study found that a Cx30 mutation that preserves half of Cx26 expression found in normal Cx30 mice resulted in unimpaired hearing.[25] The lessened severity of Cx30 knockout in comparison to Cx26 knockout is supported by a study examining the time course and patterns of hair cell degeneration in the cochlea. Cx26 null mice displayed more rapid and widespread cell death than Cx30 null mice. The percent hair cell loss was less widespread and frequent in the cochleas of Cx30 null mice.[26]

Sleep cycle

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Connexin 30 (Cx30) appears to play a crucial role in regulating sleep and wakefulness, potentially through its involvement in circadian rhythm generation, response to sleep pressure, and modulation of astrocyte morphology and function.[27][28][29]

Research has shown that Cx30 and Connexin 43 (Cx43) exhibit a time-of-day dependent expression in the mouse suprachiasmatic nucleus (SCN), the central circadian rhythm generator. These connexins contribute to the electric coupling of SCN neurons and astrocytic-neuronal signaling that regulates rhythmic SCN neuronal activity.[27][28][29]

Interestingly, the fluctuation of Cx30 protein expression strongly depends on the light-dark cycle, which suggests that Cx30 may play a role in the circadian system's light entrainment and circadian rhythm generation.[27][28][29]

In a study using Cx30 knockout mice, researchers have found that these mice exhibited a deficit in maintaining wakefulness during periods of high sleep pressure. They needed more stimuli to stay awake during gentle sleep deprivation and showed increased slow-wave sleep during instrumental sleep deprivation.[27][28][29]

Moreover, neuronal activity has been found to increase hippocampal Cx30 protein levels via a posttranslational mechanism regulating lysosomal degradation, which translated at the functional level in the activation of Cx30 hemichannels and in Cx30-mediated remodeling of astrocyte morphology independently of gap junction biochemical coupling.[27][28][29]

The clinical significance of this finding is that it can explain the mechanism of action of modafinil in its wakefulness-promoting properties.[30] Modafinil may promote wakefulness by modulating the function of astroglial connexins, specifically connexin 30, which are proteins that facilitate intercellular communication and play a role in sleep-wake regulation.[31][28][29] Connexins form channels that allow the exchange of ions and signaling molecules between cells. In the brain, they are mainly expressed by astrocytes, which help regulate neuronal activity.[27] Modafinil increases the levels of connexin 30 in the cortex, enhancing communication between astrocytes and promoting wakefulness. Conversely, connexin 30 levels decrease during sleep, contributing to the transition from wakefulness to sleep. Flecainide, a drug that blocks astroglial connexins, can enhance the effects of modafinil on wakefulness and cognition, and reduce narcoleptic episodes in animal models. These findings suggest that modafinil may exert its therapeutic effects by modulating astroglial connexins.[27][30]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000121742 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040055 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Grifa A, Wagner CA, D'Ambrosio L, Melchionda S, Bernardi F, Lopez-Bigas N, Rabionet R, Arbones M, Monica MD, Estivill X, Zelante L, Lang F, Gasparini P (September 1999). "Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus". Nature Genetics. 23 (1): 16–8. doi:10.1038/12612. PMID 10471490. S2CID 29044968.
  6. ^ Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA (April 1996). "The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q". Human Molecular Genetics. 5 (4): 543–7. doi:10.1093/hmg/5.4.543. PMID 8845850.
  7. ^ a b "Entrez Gene: GJB6 gap junction protein, beta 6".
  8. ^ Zhao HB, Kikuchi T, Ngezahayo A, White TW (2006). "Gap junctions and cochlear homeostasis". The Journal of Membrane Biology. 209 (2–3): 177–86. doi:10.1007/s00232-005-0832-x. PMC 1609193. PMID 16773501.
  9. ^ Erbe CB, Harris KC, Runge-Samuelson CL, Flanary VA, Wackym PA (April 2004). "Connexin 26 and connexin 30 mutations in children with nonsyndromic hearing loss". The Laryngoscope. 114 (4): 607–11. doi:10.1097/00005537-200404000-00003. PMID 15064611. S2CID 25847431.
  10. ^ Kikuchi T, Kimura RS, Paul DL, Takasaka T, Adams JC (April 2000). "Gap junction systems in the mammalian cochlea". Brain Research. Brain Research Reviews. 32 (1): 163–6. doi:10.1016/S0165-0173(99)00076-4. PMID 10751665. S2CID 11292387.
  11. ^ Lautermann J, ten Cate WJ, Altenhoff P, Grümmer R, Traub O, Frank H, Jahnke K, Winterhager E (December 1998). "Expression of the gap-junction connexins 26 and 30 in the rat cochlea". Cell and Tissue Research. 294 (3): 415–20. doi:10.1007/s004410051192. PMID 9799458. S2CID 24537527.
  12. ^ Yum SW, Zhang J, Valiunas V, Kanaporis G, Brink PR, White TW, Scherer SS (September 2007). "Human connexin26 and connexin30 form functional heteromeric and heterotypic channels". American Journal of Physiology. Cell Physiology. 293 (3): C1032-48. doi:10.1152/ajpcell.00011.2007. PMID 17615163. S2CID 16854059.
  13. ^ Ortolano S, Di Pasquale G, Crispino G, Anselmi F, Mammano F, Chiorini JA (December 2008). "Coordinated control of connexin 26 and connexin 30 at the regulatory and functional level in the inner ear". Proceedings of the National Academy of Sciences of the United States of America. 105 (48): 18776–81. Bibcode:2008PNAS..10518776O. doi:10.1073/pnas.0800831105. PMC 2596232. PMID 19047647.
  14. ^ Kikuchi T, Kimura RS, Paul DL, Adams JC (February 1995). "Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis". Anatomy and Embryology. 191 (2): 101–18. doi:10.1007/BF00186783. PMID 7726389. S2CID 24900775.
  15. ^ Forge A, Jagger DJ, Kelly JJ, Taylor RR (April 2013). "Connexin30-mediated intercellular communication plays an essential role in epithelial repair in the cochlea" (PDF). Journal of Cell Science. 126 (Pt 7): 1703–12. doi:10.1242/jcs.125476. PMID 23424196.
  16. ^ Pannasch U, Vargová L, Reingruber J, Ezan P, Holcman D, Giaume C, Syková E, Rouach N (2011-05-17). "Astroglial networks scale synaptic activity and plasticity". Proceedings of the National Academy of Sciences. 108 (20): 8467–8472. Bibcode:2011PNAS..108.8467P. doi:10.1073/pnas.1016650108. ISSN 0027-8424. PMC 3100942. PMID 21536893.
  17. ^ Pannasch U, Vargová L, Reingruber J, Ezan P, Holcman D, Giaume C, Syková E, Rouach N (2011-05-17). "Astroglial networks scale synaptic activity and plasticity". Proceedings of the National Academy of Sciences. 108 (20): 8467–8472. Bibcode:2011PNAS..108.8467P. doi:10.1073/pnas.1016650108. ISSN 0027-8424. PMC 3100942. PMID 21536893.
  18. ^ Rouach N, Koulakoff A, Abudara V, Willecke K, Giaume C (2008-12-05). "Astroglial Metabolic Networks Sustain Hippocampal Synaptic Transmission". Science. 322 (5907): 1551–1555. Bibcode:2008Sci...322.1551R. doi:10.1126/science.1164022. ISSN 0036-8075. PMID 19056987.
  19. ^ Chever O, Lee CY, Rouach N (2014-08-20). "Astroglial Connexin43 Hemichannels Tune Basal Excitatory Synaptic Transmission". The Journal of Neuroscience. 34 (34): 11228–11232. doi:10.1523/JNEUROSCI.0015-14.2014. ISSN 0270-6474. PMC 6615508. PMID 25143604.
  20. ^ Hardy E, Cohen-Salmon M, Rouach N, Rancillac A (2021). "Astroglial Cx30 differentially impacts synaptic activity from hippocampal principal cells and interneurons". Glia. 69 (9): 2178–2198. doi:10.1002/glia.24017. ISSN 0894-1491. PMID 33973274. Cx30 alters specific properties of certain subsets of CA1 interneurons, such as resting membrane potential and sag ratio, while other parameters, such as action potential threshold and saturation frequency, were more frequently altered across different classes of neurons. The excitation-inhibition balance was also differentially and selectively modulated among the various neuron subtypes. Therefore, astrocytes, via Cx30, actively modulate both excitatory and inhibitory synapses in the hippocampus.
  21. ^ Ribot J, Breton R, Calvo CF, Moulard J, Ezan P, Zapata J, Samama K, Moreau M, Bemelmans AP, Sabatet V, Dingli F, Loew D, Milleret C, Billuart P, Dallérac G (2021-07-02). "Astrocytes close the mouse critical period for visual plasticity". Science. 373 (6550): 77–81. Bibcode:2021Sci...373...77R. doi:10.1126/science.abf5273. ISSN 0036-8075. PMID 34210880.
  22. ^ Hardy E, Moulard J, Walter A, Ezan P, Bemelmans AP, Mouthon F, Charvériat M, Rouach N, Rancillac A (2023-04-11). Eroglu C (ed.). "Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory". PLOS Biology. 21 (4): e3002075. doi:10.1371/journal.pbio.3002075. ISSN 1545-7885. PMC 10089355. PMID 37040348.
  23. ^ Teubner B, Michel V, Pesch J, Lautermann J, Cohen-Salmon M, Söhl G, Jahnke K, Winterhager E, Herberhold C, Hardelin JP, Petit C, Willecke K (January 2003). "Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential". Human Molecular Genetics. 12 (1): 13–21. doi:10.1093/hmg/ddg001. PMID 12490528.
  24. ^ Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, Kojima K, Ichinohe A, Suzuki Y, Aoki Y, Kobayashi T, Matsubara Y (May 2003). "Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness". Human Molecular Genetics. 12 (9): 995–1004. doi:10.1093/hmg/ddg116. PMID 12700168.
  25. ^ Boulay AC, del Castillo FJ, Giraudet F, Hamard G, Giaume C, Petit C, Avan P, Cohen-Salmon M (January 2013). "Hearing is normal without connexin30". The Journal of Neuroscience. 33 (2): 430–4. doi:10.1523/JNEUROSCI.4240-12.2013. PMC 6704917. PMID 23303923.
  26. ^ Sun Y, Tang W, Chang Q, Wang Y, Kong W, Lin X (October 2009). "Connexin30 null and conditional connexin26 null mice display distinct pattern and time course of cellular degeneration in the cochlea". The Journal of Comparative Neurology. 516 (6): 569–79. doi:10.1002/cne.22117. PMC 2846422. PMID 19673007.
  27. ^ a b c d e f g Yang S, Kong XY, Hu T, Ge YJ, Li XY, Chen JT, He S, Zhang P, Chen GH (2022). "Aquaporin-4, Connexin-30, and Connexin-43 as Biomarkers for Decreased Objective Sleep Quality and/or Cognition Dysfunction in Patients With Chronic Insomnia Disorder". Front Psychiatry. 13: 856867. doi:10.3389/fpsyt.2022.856867. PMC 8989729. PMID 35401278.
  28. ^ a b c d e f Ingiosi AM, Frank MG (May 2023). "Goodnight, astrocyte: waking up to astroglial mechanisms in sleep". FEBS J. 290 (10): 2553–2564. doi:10.1111/febs.16424. PMC 9463397. PMID 35271767.
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Further reading

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