| Structure | GAL is a 29-aa C-terminally amidated peptide, apartfrom human GAL, which has 20 aa and no amidatedN-terminus. The N-terminal 1–15 aa are highlyconserved. Human proGAL: Mr 13,302.1, pI 6.84. Soluble in waterand physiological saline solution.
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| Gene, mRNA, and precursor | The GAL gene is located on human chromosome11q13.2, rat chromosome 1q42, and mouse chromosome19A. The peptide precursor of GAL is encoded by asingle-copy gene consisting of six small exons spanningabout 6 kb of genomic DNA. Regarding its structure, asequence of GAL is followed by the signal peptide, andthe remainder is called the GAL message-associatedpeptide (GMAP). GAL is widely expressed in the central and peripheralnervous systems in many mammalian species. In thebrain, GAL is synthesized in the dorsal raphe nucleus,locus coeruleus, rostral ventrolateral medulla, centralnucleus of the amygdala, paraventricular nucleus, andsupraoptic nucleus. GAL is also found in the spinal cordand gut. |
| Synthesis and release | GAL colocalizes in vasopressin neurons and increasesduring salt loading, suggesting its influence on osmotically stimulated vasopressin release. GAL gene expression in magnocellular neurons is increased by estrogen. |
| Receptors | GAL receptors have three subtypes, referred to as GALreceptor types 1, 2, and 3 (GALR1, GALR2, and GALR3).6The human GALR1 gene contains three exons and istranslated into a 349-aa protein. The homology betweenspecies is 93% for rat and human GALR1. The expressionof GALR1 is regulated by cAMP through the transcriptionfactor CREB. Human GALR2 has 92% sequence identityto rat GALR2, although there is a 15-aa extension of theC-terminal end in human GALR2. The GALR2 gene isexpressed more ubiquitously compared with that ofGALR1, as it is found in several peripheral tissues, including the pituitary gland, gastrointestinal tract, skeletalmuscle, heart, kidney, uterus, ovary, and testis, in addition to the central nervous system. The Galr3 transcriptwas first isolated from rat hypothalamic cDNA libraries.Human GALR3 consists of 368 aa and shares 36% identitywith human GALR1, 58% with human GALR2, andapproximately 90% with rat GALR3. |
| Agonists and Antagonists | M617 (GALR1), M1153, M1145 (GALR2). M35 and galantide (nonselective GALR antagonists),RWJ-57408 (GALR1), M871 (GALR2), and SNAP37889and SNAP398299 (GALR3). |
| Biological functions | In rats, GALR1 is prominently distributed in the hypothalamus, amygdala, hippocampus, thalamus, brainstem, spinal cord, dorsal root ganglion (DRG), gut,heart, lung, kidney, muscle, adipocytes, and testis.GALR2 mainly exists in the cortex, hypothalamus, hippocampus, amygdala, cerebellum, DRG, heart, liver, lung,kidney, intestine, uterus, ovary, stomach, pancreas, andtestis. GALR3 is found in the hypothalamus, dorsal raphenucleus, locus coeruleus, and amygdala. GAL is thoughtto regulate numerous physiological processes in the adultmammalian nervous system, including sleep/wake regulation, energy and osmotic homeostasis, reproduction,nociception, and cognition. |
| Clinical implications | GAL increases food intake and body weight viaGALR1. Intranasal administration is an effective routefor the delivery of GAL-related agents into the brain byuse of various cyclodextrins. Thus, the intranasal administration of a GALR1 antagonist offers an attractiveapproach to combat obesity. Clinical studies indicatedthat the GAL concentration is correlative to the morbidityof type 2 diabetes mellitus in humans. In addition,some clinical studies have shown that the activation ofthe GAL pathway is effective in treating type 2diabetes. |
| Description | GAL is expressed in the brain and peripheral organs, andhas diverse physiological actions, including energy homeostasis, reproduction, nociception, and cognition. GAL was isolated in 1983 from the porcine intestine byTatemoto and colleagues. The GAL peptide has beenpurified from the chicken, alligator, and fish species,including trout, tuna, bowfin, dogfish, and sturgeon. |
| Uses | Galanin (swine), a neuropeptide, consists of 29 amino acids and contains a C-terminal amidated glycine. Galanin (swine) inhibits basal and stimulated insulin secretion both in vivo and in vitro under a variety of experimental conditions. Galanin (swine) is a galanin receptor agonist with pKis of 9.63, 9.49, 9.02, 8.98, 8.01 and 8.14 at human GAL1, rat GAL1, human GAL2, rat GAL2, human GAL3 and rat GAL3 respectively[1]. |
| Biological Functions | Galanin iscolocalized with acetylcholine, 5-HT , and NE in neurons or in brain regions implicated in cognitive andaffective behavior, suggesting a possible role in the regulation of 5-HT and NA neurotransmission indepressive states and during the course of antidepressant therapy. Three galanin receptor subtypes havebeen cloned and studied, but little is known about their specific contributions to behavioral processes. In theCNS, galanin inhibits acetylcholine release, suggesting a possible role for galanin in cholinergic dysfunction;inhibits neurotransmitter release and neuronal firing rate; and inhibits signal transduction by inhibition ofphosphatidyl inositol hydrolysis, leading to symptoms of depression. Thus, blocking the inhibitory effects ofgalanin on monoamine neurotransmitters with galanin receptor antagonists would be predicted to mimic oraugment the action of the other monoamine classes of antidepressants." |
| Clinical Use | Since its discovery in 1983, the neuropeptide galanin has been found to be involved in a wide range offunctions, including pain sensation, sexual activity, feeding, and learning and memory. Galanin is widelydistributed in the central and peripheral nervous systems and in the endocrine system, and it acts as ainhibitory neuromodulator of NE and 5-HT in the brain. The 29- to 30-amino-acid sequence of galanin isconserved (almost 90% among species), indicating the importance of the molecule among species. |
| References | [1] Branchek TA, et al. Galanin receptor subtypes. Trends Pharmacol Sci. 2000;21(3):109-117. DOI:10.1016/s0165-6147(00)01446-2
[2] Ahrén B, et al. Galanin and the endocrine pancreas. FEBS Lett. 1988;229(2):233-237. DOI:10.1016/0014-5793(88)81131-1 |
