Galanin

edit Galanin Identifiers Symbols GAL; GALN; GLNN; MGC40167 External IDs OMIM: 137035 MGI: 95637 HomoloGene: 7724 GeneCards: GAL Gene Gene Ontology Molecular function • neuropeptide hormone activity Cellular component • extracellular region Biological process • smooth muscle contraction • neuropeptide signaling pathway • nervous system development • insulin secretion • growth hormone secretion Sources: Amigo / EGO RNA expression pattern 250px More reference expression data Orthologs Species Human Mouse Entrez 51083 14419 Ensembl ENSG00000069482 ENSMUSG00000024907 UniProt P22466 Q3V002 RefSeq (mRNA) NM_015973 NM_010253 RefSeq (protein) NP_057057 NP_034383 Location (UCSC) Chr 11: 68.21 - 68.22 Mb Chr 19: 3.41 - 3.41 Mb PubMed search [1] [2]

Galanin is a neuropeptide that is encoded by the GAL gene, 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.

The functional role of galanin, along with most other neuropeptides, 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. Galanin is linked to a number of diseases including Alzheimer’s disease, epilepsy as well as depression, eating disorders and cancer. 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.

Galanin is predominantly an inhibitory, hyperpolarizing neuropeptide 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.

Discovery

Galanin was first identified from porcine intestinal extracts in 1978 by Professor Viktor Mutt and colleagues at the Karolinska Institute, Sweden 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. 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.

Tissue distribution

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.

Structure

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 *
Man	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 known as preprogalanin, which is encoded by the GAL gene. The sequence of this gene is highly conserved amongst mammals, showing over 85% homology between rat, mouse, porcine, bovine and human sequences. 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.

Galanin Identifiers Symbol Galanin Pfam PF01296 InterPro IPR008174 PROSITE PDOC00673

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. 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.

Receptors

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

Clinical characteristics

Alzheimer’s Disease

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. 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. The cause and role of this increase is poorly understood.

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.

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. Interestingly, 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 whether galanin acts to protect cholinergic neurons and promote their firing or whether it worsens the symptoms of this disease.

Epilepsy

Galanin in the hippocampus is an inhibitor of glutamate but not GABA and as such is capable of increasing the seizure threshold and therefore is expected to act as an anticonvulsant. Specifically, GalR1 has been linked to the suppression of spontaneous seizures. Agonist antiepileptic drug candidate NAX 5055.

In development

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). 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

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 neuritis 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.

See also

• galanin receptor

Further reading

• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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 Freely accessible. PMID 1722333. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
• 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. CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

External links

• MeSH Galanin

de:Galanin pt:Galanina