Alternative titles; symbols
HGNC Approved Gene Symbol: GAL
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38): 11:68,684,544-68,691,175 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | ?Epilepsy, familial temporal lobe, 8 | 616461 | Autosomal dominant | 3 |
Galanin is small neuropeptide that functions as a cellular messenger within the central and peripheral nervous systems, modulating diverse physiologic functions (summary by Mechenthaler, 2008).
Schmidt et al. (1991) isolated the mature galanin peptide from human pituitary. Unlike the 29-amino acid porcine, rat, and bovine Gals, which contain a C-terminal amidated glycine, mature human GAL contains 30 amino acids and has a C-terminal nonamidated serine. By mass spectrometry, Schmidt et al. (1991) determined that mature human GAL has a mass of 3,156.1 Da.
Bersani et al. (1991) isolated 2 GAL peptides from normal human colon: a 19-amino acid peptide with a calculated molecular mass of 1,964 Da, and a 30-amino acid peptide with a calculated molecular mass of 3,157 Da. The smaller peptide is identical to the N terminus of the larger peptide, and the first 15 amino acids of both are identical to those of porcine, rat, and bovine Gal.
By PCR of human pituitary and neuroblastoma cell line cDNA libraries, Evans and Shine (1991) cloned full-length preprogalanin cDNA. The deduced 123-amino acid protein contains an N-terminal signal sequence, followed by a short propeptide, the mature 30-amino acid galanin peptide, and a C-terminal sequence homologous to rat, porcine, and bovine galanin mRNA-associated peptide (GMAP). Evans and Shine (1991) suggested that the presence of gly at position 17 in human galanin may be significant, since this residue is aspartic acid in all other species examined.
McKnight et al. (1992) cloned human galanin from pheochromocytoma mRNA.
Using Northern blot analysis, Ormandy et al. (1998) detected a major 0.9-kb preprogalanin mRNA in 8 of 8 estrogen receptor (ESR; see 133430)-positive and 8 of 12 ESR-negative breast cancer cell lines examined.
Lundkvist et al. (1995) used RT-PCR to clone galanin from mouse hypothalamic cDNA. They determined the galanin sequence as well as that of the flanking peptide Gmap, which is encoded on the same mRNA. The N-terminal 14 amino acids of mouse galanin are identical to those in human, porcine, dog, rat, bovine, chicken, sheep, alligator, bowfin, dogfish, trout, and mouse.
Schmidt et al. (1991) synthesized GAL peptides identical to mature human GAL and an amidated derivative of GAL. Both peptides bound equally well to the rat insulinoma Gal receptor (see GALR1; 600377) and elicited contractions of isolated longitudinal rat fundus strips.
Lopez et al. (1991) noted that, in brain, highest concentrations of galanin are in the hypothalamus and in the nerve terminals of the median eminence. Since the establishment of the neurovascular concept in the regulation of the hypothalamus-pituitary axis (Harris, 1948), it has been known that the median eminence represents a key area for neuroendocrine regulation. Hypothalamic releasing and inhibiting factors are secreted from median eminence terminals into the portal circulation to reach the adenohypophyseal cells where they exert specific actions. Lopez et al. (1991) measured Gal and Lhrh (GNRH1; 152760) levels in rat hypophyseal portal plasma and found that both hormones were released in male and female rats in a pulsatile manner with a frequency of 1 pulse per hour. Lopez et al. (1991) also identified Gal neurons in the hypothalamus, including a subset of neurons expressing Gal and Lhrh, strengthening the notion of the existence of a GAL neuronal system connected to the hypophyseal portal circulation. Rat Gal induced a small but dose-dependent increase in Lh (see 152780) secretion from cultured rat pituitary cells and enhanced the ability of Lhrh to stimulate Lh release. During the rat estrous cycle, the concentrations of Gal and Lhrh in the median eminence showed an identical profile (r = 1.00). Lopez et al. (1991) concluded that GAL is a hypothalamic-hypophysiotropic hormone and is a neuromodulator of LHRH secretion and action.
Rattan (1991) showed that galanin is important to gastrointestinal function.
McKnight et al. (1992) showed that synthetic human galanin, as well as rat and porcine galanin, inhibited glucose-stimulated insulin (INS; 176730) release from a rat insulinoma cell line. None of the galanins studied inhibited basal insulin secretion. At the highest glucose concentration used, 5.6 mM, each galanin inhibited insulin release about 50%. At lower glucose concentrations, weaker inhibition was observed.
Avrat et al. (1995) found that intravenous infusion of porcine galanin in 7 normal young women, aged 25 to 30 years, caused an increase in serum GH (139250) levels, but failed to significantly modify spontaneous secretion of prolactin (PRL; 176760), LH, FSH (see 136530), TSH (see 188540), ACTH (see 176830), or cortisol.
Grottoli et al. (1996) found that porcine galanin infusion in 6 normal young women, aged 23 to 35 years and in their early follicular phase, failed to significantly increase basal PRL levels, but it enhanced the PRL response to TRH or arginine infusion. Galanin did not modify the PRL response to dopamine receptor (see 126449) blockade. Grottoli et al. (1996) concluded that galanin is unlikely to influence PRL secretion via inhibition of dopaminergic tone.
Degli Uberti et al. (1996) found that infusion of human GAL over 60 minutes in 9 healthy volunteers blunted the release of norepinephrine and pancreatic polypeptide (PPY; 167780) in response to oral pyridostigmine bromide (PD), an acetylcholinesterase inhibitor. GAL also prevented PD-induced slowing of the heart rate, but it failed to modulate PD-evoked epinephrine release. Neither PD nor GAL altered supine systolic and diastolic blood pressure. Degli Uberti et al. (1996) proposed a functional interrelationship between GAL and the cholinergic system.
Ormandy et al. (1998) found that ESR-positive breast cancer cell lines expressed moderate amounts of preprogalanin mRNA, whereas levels in ESR-negative cell lines were either very high or very low to absent, suggesting steroid hormones regulate preprogalanin expression. The GAL gene was amplified in a subset of breast cancers carrying 11q13 amplification, but GAL amplification did not lead to increased preprogalanin mRNA levels. Treatment of breast cancer cells with estradiol and progestin increased preprogalanin mRNA expression, whereas serum withdrawal or treatment with antiestrogens decreased preprogalanin mRNA expression. Ormandy et al. (1998) concluded that preprogalanin expression is under steroid hormone control in ESR-positive cells.
Wynick et al. (1998) stated that galanin is predominantly expressed by lactotrophs (the prolactin-secreting cell type) in the rodent anterior pituitary and in the median eminence and paraventricular nucleus of the hypothalamus. Prolactin and galanin colocalize in the same secretory granule, and expression of both proteins is extremely sensitive to the estrogen status of the animal. Administration of estradiol-17-beta induces pituitary hyperplasia followed by adenoma formation and causes a 3,000-fold increase in the galanin mRNA content of the lactotroph.
Naylor et al. (2003) showed that treatment with galanin plus prolactin caused the formation of larger and more numerous lobules in mouse mammary organ cultures than did treatment with prolactin alone. Galanin alone produced sustained activation of Stat5a (601511) and induced milk protein expression, but it did not induce lobulogenesis. Microarray analysis of cultured mouse mammary glands revealed 3 major sets of genes regulated by galanin and/or prolactin: those that were independently regulated by galanin and prolactin; those that were regulated by galanin plus prolactin, but by neither hormone alone; and those that were regulated by prolactin regardless of the presence of galanin. Many fewer genes were regulated by galanin alone than were regulated by prolactin alone, and prolactin antagonized expression of nearly all galanin-regulated genes. Galanin did not induce prolactin or prolactin receptor (PRLR; 176761) gene expression, and prolactin did not regulate expression of galanin or its receptors.
In mice, Wu et al. (2014) uncovered a subset of galanin-expressing neurons in the medial preoptic area (MPOA) that are specifically activated during male and female parenting, and a different subpopulation that is activated during mating. Genetic ablation of MPOA galanin neurons results in marked impairment of parental responses in males and females and affects male mating. Optogenetic activation of these neurons in virgin males suppresses intermale and pup-directed aggression and induces pup grooming. Thus, Wu et al. (2014) concluded that MPOA galanin neurons are an essential regulatory node of male and female parenting behavior and other social responses.
Reviews of Galanin Function
Bauer et al. (2008) reviewed expression of galanin peptides in human skin and the roles of galanin peptides in immunity, inflammation, cell proliferation, and wound healing.
Mechenthaler (2008) reviewed the neuroendocrine functions of galanin and noted differences in cell- and gender-specific expression of galanin in humans compared with other species.
Evans et al. (1993) cloned and characterized a 35-kb region of genomic DNA encoding the human preprogalanin gene, including 5-prime and 3-prime flanking sequences. The gene spans 6.5 kb and contains 6 exons. The first exon contains only the 5-prime UTR.
Kofler et al. (1995) determined that the 5-prime flanking sequence of the GAL gene contains a CT-rich region, flanked by 2 Alu repeats, 2.3 kb upstream of the transcriptional start site. The 500-bp region preceding the transcriptional start site shows 79% GC content. The 5-prime flanking sequence has a TATA box preceded by binding sites for numerous transcription factors, including SP1 (189906), AP2 (107580), and NF-kappa-B (see 164011). It also has 3 half-palindromic estrogen response elements, but no typical CAAT box. Functional analysis demonstrated both positive and negative regulatory elements.
Using PCR with primers derived from the 3-prime end of the human cDNA sequence for the analysis of deletion somatic cell hybrids, Charlton et al. (1993) localized the galanin gene to the proximal short arm of chromosome 11. They confirmed the localization by fluorescence in situ hybridization. Analysis of recombinant inbred strains and an interspecific backcross localized the mouse galanin gene close to the centromere of chromosome 19. Charlton et al. (1993) commented that the results extended the region of synteny for human 11q12-q13/mouse 19 across the centromere to human 11p. They also referred to a familial syndrome associated with a cytogenetically defined interstitial deletion in region 11p12-p11.12 that exhibits a phenotype consistent with galanin insufficiency: short stature, hypogonadism, obesity, and developmental delay.
Using high-resolution fluorescence in situ hybridization, Evans et al. (1993) localized the single GALN gene to chromosome 11q13.3-q13.5. This finding is inconsistent with that of Charlton et al. (1993).
In 2 monozygotic male twins with familial temporal lobe epilepsy-8 (ETL8; 616461), Guipponi et al. (2015) identified a de novo heterozygous missense mutation in the GAL gene (A39E; 137035.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro functional studies showed that the mutant protein had antagonistic activity against GALR1-mediated responses as well as decreased binding affinity and reduced agonist properties for GALR2 (603691). These findings suggested that the mutant protein could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to epilepsy. Sequencing of the GAL gene in a cohort of 582 additional patients with epilepsy did not identify any mutations.
To study the role of galanin in prolactin release and lactotroph growth, Wynick et al. (1998) generated mice carrying a loss-of-function mutation of the endogenous galanin gene. There was no evidence of embryonic lethality and the mutant mice grew normally. The specific endocrine abnormalities identified related to the expression of prolactin. Pituitary prolactin message levels and protein content of adult female mutant mice were reduced by 30 to 40% compared with wildtype controls. Mutant females failed to lactate and pups died of starvation/dehydration unless fostered onto wildtype mothers. Prolactin secretion in mutant females was markedly reduced at 7 days postpartum compared with wildtype controls with an associated failure in mammary gland maturation. There was almost complete abrogation of the proliferative response of the lactotroph to high doses of estrogen, with a failure to upregulate prolactin release and STAT5 (601511) expression or to increase pituitary cell number. These data supported the hypothesis that galanin acts as a paracrine regulator of prolactin expression and as a growth factor to the lactotroph.
Naylor et al. (2003) showed that prolactin treatment of galanin-knockout mice allowed pup survival, but it did not completely rescue lobuloalveolar development or reduced milk protein expression. Using mammary epithelial transplantation, Naylor et al. (2003) showed that normal circulating galanin was sufficient for normal mammary gland development in the absence of mammary-produced galanin.
Holmes et al. (2000) reported that adult mice homozygous for a targeted loss-of-function mutation in the galanin gene had a 13% reduction in the number of cells in the dorsal root ganglion associated with a 24% decrease in the percentage of neurons that express substance P (162320). After crush injury to the sciatic nerve, the rate of peripheral nerve regeneration was reduced by 35% with associated long-term functional deficits. These results identified a critical role for galanin in the development and regeneration of sensory neurons.
Galanin colocalizes with choline acetyltransferase (CHAT; 118490), the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor (e.g., NGF; 162030) induces a 3- to 4-fold increase in galanin gene expression in these neurons. O'Meara et al. (2000) reported the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits were associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day 7. The data provided unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons.
In Alzheimer disease (104300), increased galanin-containing fibers hyperinnervate cholinergic neurons within the basal forebrain in association with a decline in cognition. To study the neurochemical and behavioral sequelae of a mouse model of galanin overexpression in Alzheimer disease, Steiner et al. (2001) generated transgenic mice that overexpressed galanin under the control of the dopamine beta-hydroxylase (223360) promoter. Overexpression of galanin was associated with a reduction in the number of identifiable neurons producing acetylcholine in the horizontal limb of the diagonal band. Behavioral phenotyping indicated that the transgenic mice displayed normal general health and sensory and motor abilities; however, they showed selective performance deficits on the Morris spatial navigational task and the social transmission of food preference olfactory memory test. These results suggested that elevated expression of galanin contributes to the neurochemical and cognitive impairments characteristic of Alzheimer disease.
To understand the further the role played by galanin in nociception, Holmes et al. (2003) generated 2 transgenic lines that overexpress galanin in specific populations of primary afferent dorsal root ganglia neurons in either an inducible or constitutive manner. The results of a variety of experiments supported an inhibitory role for galanin in the modulation of nociception both in intact animals and in neuropathic pain states.
Lerner et al. (2008) reviewed the role of galanin in animal models of epilepsy, where it functions as an anticonvulsant.
In 2 monozygotic male twins with familial temporal lobe epilepsy-8 (ETL8; 616461), Guipponi et al. (2015) identified a de novo heterozygous c.116C-A transversion (c.116C-A, NM_015973.3) in the GAL gene, resulting in an ala39-to-glu (A39E) substitution in the GAL propeptide that corresponds to the highly conserved seventh residue of the 30-amino acid mature GAL peptide. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 138) or ExAC databases. In vitro functional studies showed that the mutant protein had antagonistic activity against GALR1 (600377)-mediated responses as well as decreased binding affinity and reduced agonist properties for GALR2 (603691). These findings suggested that the mutant protein could impair galanin signaling in the hippocampus, leading to increased glutamatergic excitation and ultimately to epilepsy.
Avrat, E., Gianotti, L., Ramunni, J., Grottoli, S., Brossa, P. C., Bertagna, A., Camanni, F., Ghigo, E. Effect of galanin on basal and stimulated secretion of prolactin, gonadotropins, thyrotropin, adrenocorticotropin and cortisol in humans. Europ. J. Endocr. 133: 300-304, 1995. [PubMed: 7581945] [Full Text: https://doi.org/10.1530/eje.0.1330300]
Bauer, J. W., Lang, R., Jakab, M., Kofler, B. Galanin family of peptides in skin function. Cell. Molec. Life Sci. 65: 1820-1825, 2008. [PubMed: 18500644] [Full Text: https://doi.org/10.1007/s00018-008-8156-5]
Bersani, M., Johnsen, A. H., Hojrup, P., Dunning, B. E., Andreasen, J. J., Holst, J. J. Human galanin: primary structure and identification of two molecular forms. FEBS Lett. 283: 189-194, 1991. [PubMed: 1710578] [Full Text: https://doi.org/10.1016/0014-5793(91)80585-q]
Charlton, P., Guida, L., Copeland, N., Jenkins, N., Munroe, D., Greenberg, F., Fiedorek, F. T., Nicholls, R. D. Genetic approach to function of the neuropeptide galanin. (Abstract) Am. J. Hum. Genet. 53 (suppl.): A1137, 1993.
degli Uberti, E. C., Bondanelli, M., Margutti, A., Ambrosio, M. R., Valentini, A., Campo, M., Franceschetti, P., Zatelli, M. C., Pansini, R., Trasforini, G. Acute administration of human galanin in normal subjects reduces the potentiating effect of pyridostigmine-induced cholinergic enhancement on release of norepinephrine and pancreatic polypeptide. Neuroendocrinology 64: 398-404, 1996. [PubMed: 8930940] [Full Text: https://doi.org/10.1159/000127143]
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Grottoli, S., Arvat, E., Gianotti, L., Ramunni, J., Di Vito, L., Maccagno, B., Ciccarelli, E., Camanni, F., Ghigo, E. Galanin positively modulates prolactin secretion in normal women. J. Endocr. Invest. 19: 739-744, 1996. [PubMed: 9061507] [Full Text: https://doi.org/10.1007/BF03347877]
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Harris, G. W. Neural control of the pituitary gland. Physiol. Rev. 28: 139-179, 1948. [PubMed: 18865220] [Full Text: https://doi.org/10.1152/physrev.1948.28.2.139]
Holmes, F. E., Bacon, A., Pope, R. J. P., Vanderplank, P. A., Kerr, N. C. H., Sukumaran, M., Pachnis, V., Wynick, D. Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior. Proc. Nat. Acad. Sci. 100: 6180-6185, 2003. [PubMed: 12721371] [Full Text: https://doi.org/10.1073/pnas.0937087100]
Holmes, F. E., Mahoney, S., King, V. R., Bacon, A., Kerr, N. C. H., Pachnis, V., Curtis, R., Priestley, J. V., Wynick, D. Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity. Proc. Nat. Acad. Sci. 97: 11563-11568, 2000. [PubMed: 11016970] [Full Text: https://doi.org/10.1073/pnas.210221897]
Kofler, B., Evans, H. F., Liu, M. L., Falls, V., Iismaa, T. P., Shine, J., Herzog, H. Characterization of the 5-prime-flanking region of the human preprogalanin gene. DNA Cell Biol. 14: 321-329, 1995. [PubMed: 7536007] [Full Text: https://doi.org/10.1089/dna.1995.14.321]
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Lopez, F. J., Merchenthaler, I., Ching, M., Wisniewski, M. G., Negro-Vilar, A. Galanin: a hypothalamic-hypophysiotropic hormone modulating reproductive functions. Proc. Nat. Acad. Sci. 88: 4508-4512, 1991. [PubMed: 1709744] [Full Text: https://doi.org/10.1073/pnas.88.10.4508]
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Mechenthaler, I. Galanin and the neuroendocrine axes. Cell. Molec. Life Sci. 65: 1826-1835, 2008. [PubMed: 18500643] [Full Text: https://doi.org/10.1007/s00018-008-8157-4]
Naylor, M. J., Ginsburg, E., Iismaa, T. P., Vonderhaar, B. K., Wynick, D., Ormandy, C. J. The neuropeptide galanin augments lobuloalveolar development. J. Biol. Chem. 278: 29145-29152, 2003. [PubMed: 12759342] [Full Text: https://doi.org/10.1074/jbc.M303746200]
O'Meara, G., Coumis, U., Ma, S. Y., Kehr, J., Mahoney, S., Bacon, A., Allen, S. J., Holmes, F., Kahl, U., Wang, F. H., Kearns, I. R., Ove-Ogren, S., Dawbarn, D., Mufson, E. J., Davies, C., Dawson, G., Wynick, D. Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons. Proc. Nat. Acad. Sci. 97: 11569-11574, 2000. [PubMed: 11016971] [Full Text: https://doi.org/10.1073/pnas.210254597]
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Schmidt, W. E., Kratzin, H., Eckart, K., Drevs, D., Mundkowski, G., Clemens, A., Katsoulis, S., Schafer, H., Gallwitz, B., Creutzfeldt, W. Isolation and primary structure of pituitary human galanin, a 30-residue nonamidated neuropeptide. Proc. Nat. Acad. Sci. 88: 11435-11439, 1991. [PubMed: 1722333] [Full Text: https://doi.org/10.1073/pnas.88.24.11435]
Steiner, R. A., Hohmann, J. G., Holmes, A., Wrenn, C. C., Cadd, G., Jureus, A., Clifton, D. K., Luo, M., Gutshall, M., Ma, S. Y., Mufson, E. J., Crawley, J. N. Galanin transgenic mice display cognitive and neurochemical deficits characteristic of Alzheimer's disease. Proc. Nat. Acad. Sci. 98: 4184-4189, 2001. [PubMed: 11259657] [Full Text: https://doi.org/10.1073/pnas.061445598]
Wu, Z., Autry, A. E., Bergan, J. F., Watabe-Uchida, M., Dulac, C. G. Galanin neurons in the medial preoptic area govern parental behaviour. Nature 509: 325-330, 2014. [PubMed: 24828191] [Full Text: https://doi.org/10.1038/nature13307]
Wynick, D., Small, C. J., Bacon, A., Holmes, F. E., Norman, M., Ormandy, C. J., Kilic, E., Kerr, N. C. H., Ghatei, M., Talamantes, F., Bloom, S. R., Pachnis, V. Galanin regulates prolactin release and lactotroph proliferation. Proc. Nat. Acad. Sci. 95: 12671-12676, 1998. [PubMed: 9770544] [Full Text: https://doi.org/10.1073/pnas.95.21.12671]