Galanin

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Galanin/GMAP prepropeptide
Identifiers
Symbols GAL ; GAL-GMAP; GALN; GLNN; GMAP
External IDs OMIM137035 MGI95637 HomoloGene7724 GeneCards: GAL Gene
RNA expression pattern
PBB GE GAL 214240 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 51083 14419
Ensembl ENSG00000069482 ENSMUSG00000024907
UniProt P22466 P47212
RefSeq (mRNA) NM_015973 NM_010253
RefSeq (protein) NP_057057 NP_034383
Location (UCSC) Chr 11:
68.45 – 68.46 Mb
Chr 19:
3.41 – 3.41 Mb
PubMed search [1] [2]
Galanin
Clinical data
Legal status ?
Identifiers
CAS number 88813-36-9 N
ATC code ?
ChEMBL CHEMBL501079 YesY
Chemical data
Formula C146H213N43O40 
Mol. mass 3210.56 g/mol
 N (what is this?)  (verify)

Galanin is a neuropeptide encoded by the GAL gene,[1] that is widely expressed in the brain, spinal cord, and gut of humans as well as other mammals. Galanin signaling occurs through three G protein-coupled receptors.[2]

The functional role of galanin remains largely unknown; however, galanin is predominately involved in the modulation and inhibition of action potentials in neurons. Galanin has been implicated in many biologically diverse functions, including: nociception, waking and sleep regulation, cognition, feeding, regulation of mood, regulation of blood pressure, it also has roles in development as well as acting as a trophic factor.[3] Galanin neurons in the medial preoptic area of the hypothalamus may govern parental behaviour.[4] Galanin is linked to a number of diseases including Alzheimer's disease, epilepsy as well as depression, eating disorders and cancer.[5][6] Galanin appears to have neuroprotective activity as its biosynthesis is increased 2-10 fold upon axotomy in the peripheral nervous system as well as when seizure activity occurs in the brain. It may also promote neurogenesis.[2]

Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide[7] and as such inhibits neurotransmitter release. Galanin is often co-localized with classical neurotransmitters such as acetylcholine, serotonin, and norepinephrine, and also with other neuromodulators such as neuropeptide Y, substance P, and vasoactive intestinal peptide.[8]

Discovery[edit]

Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden[9] using a chemical assay technique that detects peptides according to its C-terminal alanine amide structure. Galanin is so-called because it contains an N-terminal glycine residue and a C-terminal alanine.[10] The structure of galanin was determined in 1983 by the same team, and its cDNA of galanin was cloned from rat anterior pituitary library in 1987.[9]

Tissue distribution[edit]

Galanin is located predominantly in the central nervous system and gastrointestinal tract. Within the central nervous system, highest concentrations are found in the hypothalamus, with lower levels in the cortex and brainstem. Gastrointestinal galanin is most abundant in the duodenum, with lower concentrations in the stomach, small intestine, and colon.[11]

Structure[edit]

Endogenously occurring galanin sequences
Species 1 6 11 16 21 26 !
Pig G W T L N S A G Y L L G P H A I D N H R S F H D K Y G L A *
Human G W T L N S A G Y L L G P H A V G N H R S F S D K N G L T S **
Cow G W T L N S A G Y L L G P H A L D S H R S F Q D K H G L A *
Rat G W T L N S A G Y L L G P H A I D N H R S F S D K H G L T*
* C-terminal amide ** C-terminal free acid

Galanin is a peptide consisting of a chain of 29 amino acids (30 amino acids in humans) produced from the cleavage of a 123-amino acid protein known as preprogalanin, which is encoded by the GAL gene.[1] The sequence of this gene is highly conserved among mammals, showing over 85% homology between rat, mouse, porcine, bovine, and human sequences.[8] In these animal forms, the first 15 amino acids from the N-terminus are identical, but amino acids differ at several positions on the C-terminal end of the protein.

These slight differences in protein structure have far-reaching implications on their function. For example, porcine and rat galanin inhibit glucose-induced insulin secretion in rats and dogs but have no effect on insulin secretion in humans. This demonstrates that it is essential to study the effects of galanin, and other regulatory peptides, in their autologous species.[12]

The galanin family of protein consists of four proteins, of which GAL was the first to be identified. The second was galanin message-associated protein (GMAP), a 59- or 60-amino acid peptide also formed from the cleavage of preprogalanin.[10] The other two peptides, galanin-like peptide (GALP) and alarin, were identified relatively recently and are both encoded for in the same gene, the preproGALP gene. GALP and alarin are produced by different post-translational splicing of this gene.[13]

Galanin
Identifiers
Symbol Galanin
Pfam PF01296
InterPro IPR008174
PROSITE PDOC00673
Galanin message associated peptide (GMAP)
Identifiers
Symbol GMAP
Pfam PF06540
InterPro IPR013068

Receptors[edit]

Galanin signalling occurs through three classes of receptors, GALR1, GALR2, and GALR3, which are all part of the G protein-coupled receptor (GPCR) superfamily. Galanin receptors are expressed in the central nervous system, in the pancreas, and on solid tumours. The level of expression of the different receptors varies at each location, and this distribution changes after injury to neurons.[2] Experiments into the function of the receptor subtypes involve mostly genetic knockout mice. The location of the receptor and the combination of receptors that are inhibited or stimulated heavily affect the outcome of galanin signalling.[2]

Clinical characteristics[edit]

Alzheimer's disease[edit]

One of the pathological features of the brain in the later stages of Alzheimer's disease is the presence of overgrown GAL-containing fibres innervating the surviving cholinergic neurons.[14] Another feature is an increase in the expression of GAL and GAL receptors, in which increases of up to 200% have been observed in post-mortem brains of Alzheimer's patients.[2][13] The cause and role of this increase is poorly understood.[14][15]

It has been suggested that the hyper-innervation acts to promote the death of these neurons and that the inhibitory effect of galanin on cholinergic neurons worsened the degeneration of cognitive function in patients by decreasing the amount of acetylcholine available to these neurons.[2][14]

A second hypothesis has been generated based on data that suggest GAL is involved in protecting the hippocampus from excitotoxic damage and the neurons in the cholinergic basal forebrain from amyloid toxicity.[16] It is interesting to note that studies of gene expression of CBF tissue suggests that the hyperinnervation of cholinergic neurons by GAL up regulates the transcription of factors that promote neuron function and survival. It is still unclear as to whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease.

Epilepsy[edit]

Galanin in the hippocampus is an inhibitor of glutamate but not of GABA. This means that galanin is capable of increasing the seizure threshold [2] and, therefore, is expected to act as an anticonvulsant. To be specific, GalR1 has been linked to the suppression of spontaneous seizures.[17][18] Agonist antiepileptic drug candidate NAX 5055.[19][20]

In development[edit]

It has been shown that galanin plays a role in the control of the early post-natal neural development of the dorsal root ganglion (DRG).[9] Galanin-mutant animals show a 13% decrease in the number of adult DRG cells as well as a 24% decrease in the percentage of cells expressing substance P. This suggests that the cell loss by apoptosis that usually occurs in the developing DRG is regulated by galanin and that the absence of galanin results in an increase in the number of cells that die.

After injury[edit]

In vitro experiments show that DRG cells removed from galanin mutants have impaired abilities to extend neurites in culture, in that the number of cells producing neurites is decreased by a third and the mean length of these processes was halved when compared to wild-type controls. In vivo, many of the actions of galanin in the brain after an injury are similar to those observed in the developing DRG. Adult mutant animals have been shown to be 35% less capable of regenerating the sciatic nerve after crush injury, which is linked to long-term functional problems.

Parental role in mice[edit]

Galanin-expressing neurons in the medial preoptical area of the brain would be responsible for regulating aggression towards pups by male mice. [21]

See also[edit]

References[edit]

  1. ^ a b Evans H, Baumgartner M, Shine J, Herzog H (December 1993). "Genomic organization and localization of the gene encoding human preprogalanin". Genomics 18 (3): 473–7. doi:10.1016/S0888-7543(11)80002-9. PMID 7508413. 
  2. ^ a b c d e f g Mitsukawa K, Lu X, Bartfai T (June 2008). "Galanin, galanin receptors and drug targets". Cell. Mol. Life Sci. 65 (12): 1796–805. doi:10.1007/s00018-008-8153-8. PMID 18500647. 
  3. ^ Mechenthaler I (June 2008). "Galanin and the neuroendocrine axes". Cell. Mol. Life Sci. 65 (12): 1826–35. doi:10.1007/s00018-008-8157-4. PMID 18500643. 
  4. ^ Wu, Z; Autry, A. E.; Bergan, J. F.; Watabe-Uchida, M; Dulac, C. G. (2014). "Galanin neurons in the medial preoptic area govern parental behaviour". Nature 509 (7500): 325–30. doi:10.1038/nature13307. PMC 4105201. PMID 24828191.  edit
  5. ^ Lundström L, Elmquist A, Bartfai T, Langel U (2005). "Galanin and its receptors in neurological disorders". Neuromolecular Med. 7 (1-2): 157–80. doi:10.1385/NMM:7:1-2:157. PMID 16052044. 
  6. ^ Berger A, Santic R, Hauser-Kronberger C, Schilling FH, Kogner P, Ratschek M, Gamper A, Jones N, Sperl W, Kofler B (June 2005). "Galanin and galanin receptors in human cancers". Neuropeptides 39 (3): 353–9. doi:10.1016/j.npep.2004.12.016. PMID 15944034. 
  7. ^ Ito M (September 2009). "Functional roles of neuropeptides in cerebellar circuits". Neuroscience 162 (3): 666–72. doi:10.1016/j.neuroscience.2009.01.019. PMID 19361475. 
  8. ^ a b Bartfai, T., (2000). "Galanin – A neuropeptide with important central nervous system actions". Retrieved November 19, 2009. 
  9. ^ a b c Wynick D, Thompson SW, McMahon SB (February 2001). "The role of galanin as a multi-functional neuropeptide in the nervous system". Current Opinion in Pharmacology 1 (1): 73–7. doi:10.1016/S1471-4892(01)00006-6. PMID 11712539. 
  10. ^ a b Hökfelt T, Tatemoto K (June 2008). "Galanin--25 years with a multitalented neuropeptide". Cell. Mol. Life Sci. 65 (12): 1793–5. doi:10.1007/s00018-008-8152-9. PMID 18500648. 
  11. ^ Kaplan LM, Spindel ER, Isselbacher KJ, Chin WW (February 1988). "Tissue-specific expression of the rat galanin gene". Proc. Natl. Acad. Sci. U.S.A. 85 (4): 1065–9. doi:10.1073/pnas.85.4.1065. PMC 279702. PMID 2448788. 
  12. ^ Bersani M, Johnsen AH, Højrup P, Dunning BE, Andreasen JJ, Holst JJ (June 1991). "Human galanin: primary structure and identification of two molecular forms". FEBS Lett. 283 (2): 189–94. doi:10.1016/0014-5793(91)80585-Q. PMID 1710578. 
  13. ^ a b Lang R, Gundlach AL, Kofler B (August 2007). "The galanin peptide family: receptor pharmacology, pleiotropic biological actions, and implications in health and disease". Pharmacol. Ther. 115 (2): 177–207. doi:10.1016/j.pharmthera.2007.05.009. PMID 17604107. 
  14. ^ a b c Counts SE, Perez SE, Mufson EJ (June 2008). "Galanin in Alzheimer's disease: neuroinhibitory or neuroprotective?". Cell. Mol. Life Sci. 65 (12): 1842–53. doi:10.1007/s00018-008-8159-2. PMC 2911017. PMID 18500641. 
  15. ^ Counts SE, Perez SE, Ginsberg SD, De Lacalle S, Mufson EJ (May 2003). "Galanin in Alzheimer disease". Mol. Interv. 3 (3): 137–56. doi:10.1124/mi.3.3.137. PMID 14993421. 
  16. ^ Ding X, MacTavish D, Kar S, Jhamandas JH (February 2006). "Galanin attenuates beta-amyloid (Abeta) toxicity in rat cholinergic basal forebrain neurons". Neurobiol. Dis. 21 (2): 413–20. doi:10.1016/j.nbd.2005.08.016. PMID 16246567. 
  17. ^ Mazarati A, Lu X, Shinmei S, Badie-Mahdavi H, Bartfai T (2004). "Patterns of seizures, hippocampal injury and neurogenesis in three models of status epilepticus in galanin receptor type 1 (GalR1) knockout mice". Neuroscience 128 (2): 431–41. doi:10.1016/j.neuroscience.2004.06.052. PMC 1360211. PMID 15350653. 
  18. ^ Zhang L, Robertson CR, Green BR, Pruess TH, White HS, Bulaj G (February 2009). "Structural Requirements for a Lipoamino Acid in Modulating the Anticonvulsant Activities of Systemically Active Galanin Analogues". Journal of Medicinal Chemistry 52 (5): 1310–6. doi:10.1021/jm801397w. PMC 2765488. PMID 19199479. 
  19. ^ Bulaj G, Green BR, Lee HK, Robertson CR, White K, Zhang L, Sochanska M, Flynn SP, Scholl EA, Pruess TH, Smith MD, White HS (December 2008). "Design, synthesis, and characterization of high-affinity, systemically-active galanin analogues with potent anticonvulsant activities". Journal of Medicinal Chemistry 51 (24): 8038–47. doi:10.1021/jm801088x. PMID 19053761. 
  20. ^ White HS, Scholl EA, Klein BD, Flynn SP, Pruess TH, Green BR, Zhang L, Bulaj G (April 2009). "Developing novel antiepileptic drugs: characterization of NAX 5055, a systemically-active galanin analog, in epilepsy models". Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics 6 (2): 372–80. doi:10.1016/j.nurt.2009.01.001. PMID 19332332. 
  21. ^ http://phys.org/news/2014-05-chemicals-neurons-responsible-parental-mice.html

Further reading[edit]

  • Vrontakis ME (2003). "Galanin: a biologically active peptide.". Current drug targets. CNS and neurological disorders 1 (6): 531–41. doi:10.2174/1568007023338914. PMID 12769595. 
  • Mufson EJ, Counts SE, Perez SE, Binder L (2005). "Galanin plasticity in the cholinergic basal forebrain in Alzheimer's disease and transgenic mice.". Neuropeptides 39 (3): 233–7. doi:10.1016/j.npep.2004.12.005. PMID 15893372. 
  • Robinson JK, Bartfai T, Langel U (2006). "Galanin/GALP receptors and CNS homeostatic processes.". CNS & neurological disorders drug targets 5 (3): 327–34. doi:10.2174/187152706777452281. PMID 16787232. 
  • McKnight GL, Karlsen AE, Kowalyk S, et al. (1992). "Sequence of human galanin and its inhibition of glucose-stimulated insulin secretion from RIN cells.". Diabetes 41 (1): 82–7. doi:10.2337/diabetes.41.1.82. PMID 1370155. 
  • Gai WP, Geffen LB, Blessing WW (1990). "Galanin immunoreactive neurons in the human hypothalamus: colocalization with vasopressin-containing neurons.". J. Comp. Neurol. 298 (3): 265–80. doi:10.1002/cne.902980302. PMID 1698834. 
  • Burleigh DE, Furness JB (1991). "Distribution and actions of galanin and vasoactive intestinal peptide in the human colon.". Neuropeptides 16 (2): 77–82. doi:10.1016/0143-4179(90)90115-F. PMID 1701228. 
  • Fried G, Meister B, Rådestad A (1991). "Peptide-containing nerves in the human pregnant uterine cervix: an immunohistochemical study exploring the effect of RU 486 (mifepristone).". Hum. Reprod. 5 (7): 870–6. PMID 1702449. 
  • Hyde JF, Engle MG, Maley BE (1991). "Colocalization of galanin and prolactin within secretory granules of anterior pituitary cells in estrogen-treated Fischer 344 rats.". Endocrinology 129 (1): 270–6. doi:10.1210/endo-129-1-270. PMID 1711463. 
  • Bennet WM, Hill SF, Ghatei MA, Bloom SR (1991). "Galanin in the normal human pituitary and brain and in pituitary adenomas.". J. Endocrinol. 130 (3): 463–7. doi:10.1677/joe.0.1300463. PMID 1719117. 
  • Schmidt WE, Kratzin H, Eckart K, et al. (1992). "Isolation and primary structure of pituitary human galanin, a 30-residue nonamidated neuropeptide.". Proc. Natl. Acad. Sci. U.S.A. 88 (24): 11435–9. doi:10.1073/pnas.88.24.11435. PMC 53150. PMID 1722333. 
  • Bauer FE, Christofides ND, Hacker GW, et al. (1986). "Distribution of galanin immunoreactivity in the genitourinary tract of man and rat.". Peptides 7 (1): 5–10. doi:10.1016/0196-9781(86)90052-5. PMID 2423990. 
  • Bauer FE, Adrian TE, Christofides ND, et al. (1986). "Distribution and molecular heterogeneity of galanin in human, pig, guinea pig, and rat gastrointestinal tracts.". Gastroenterology 91 (4): 877–83. PMID 2427385. 
  • Tainio H, Vaalasti A, Rechardt L (1987). "The distribution of substance P-, CGRP-, galanin- and ANP-like immunoreactive nerves in human sweat glands.". Histochem. J. 19 (6-7): 375–80. doi:10.1007/BF01680455. PMID 2444569. 
  • Maggi CA, Santicioli P, Patacchini R, et al. (1988). "Galanin: a potent modulator of excitatory neurotransmission in the human urinary bladder.". Eur. J. Pharmacol. 143 (1): 135–7. doi:10.1016/0014-2999(87)90744-8. PMID 2446889. 
  • Marti E, Gibson SJ, Polak JM, et al. (1988). "Ontogeny of peptide- and amine-containing neurones in motor, sensory, and autonomic regions of rat and human spinal cord, dorsal root ganglia, and rat skin.". J. Comp. Neurol. 266 (3): 332–59. doi:10.1002/cne.902660304. PMID 2447134. 
  • Beal MF, Clevens RA, Chattha GK, et al. (1988). "Galanin-like immunoreactivity is unchanged in Alzheimer's disease and Parkinson's disease dementia cerebral cortex.". J. Neurochem. 51 (6): 1935–41. doi:10.1111/j.1471-4159.1988.tb01181.x. PMID 2460590. 
  • Berrettini WH, Kaye WH, Sunderland T, et al. (1989). "Galanin immunoreactivity in human CSF: studies in eating disorders and Alzheimer's disease.". Neuropsychobiology 19 (2): 64–8. doi:10.1159/000118436. PMID 2465504. 

External links[edit]