GALP

Official Full Name

galanin like peptide

Organism

Homo sapiens

GeneID

85569

Background

This gene encodes a member of the galanin family of neuropeptides. The encoded protein binds galanin receptors 1, 2 and 3 with the highest affinity for galanin receptor 3 and has been implicated in biological processes involving the central nervous system including hypothalamic regulation of metabolism and reproduction. A peptide encoded by a splice variant of this gene, termed alarin, has vasoactive properties, displays antimicrobial activity against E. coli, and may serve as a marker for neuroblastic tumors.[provided by RefSeq, Nov 2014]

Synonyms

GALP; GAL;

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Detailed Information

Galanin was originally isolated and characterized by Tatemoto et al. Galanin has a number of functions both peripherally and centrally; chief among them galanin regulates hypothalamic secretagogues that change the release of anterior pituitary hormones. Galanin also has regulatory actions on nociception, energy homeostasis (feeding, body weight and metabolism regulation), and learning and memory. Sixteen years after the discovery of galanin, Ohtaki et al. isolated another peptide from the porcine hypothalamus that bound to the galanin receptors. They dubbed this new peptide galanin-like peptide, or GALP. GALP not only bound to these two galanin receptors with relatively high affinity in vitro but also activated these receptors similarly to galanin, and it is now known that GALP also activates GalR3. Moreover, GALP binds to and activates the GalR2 receptor with greater affinity than does galanin. Therefore, a peptide was discovered that bound to and activated galanin receptors in vitro. These exciting findings led researchers to study the genetic and structural relationships between galanin and GALP.

GALP and its receptors

The GALP gene consists of six exons with a structural organization similar to that of galanin. GALP is encoded by a distinct gene located on chromosome 19 in humans, chromosome 7 in mice and chromosome 1 in rat. Although the existence of a putative receptor for endogenous GALP has been suggested, the molecular identity of this receptor remains unknown. The members of the galanin peptide family were initially described as high affinity agonists for both GALR1 and GALR2, with GALP binding preferentially to GALR2. In a later study, binding of GALP was observed at all three human galanin receptor subtypes expressed in human neuroblastoma cells, with the highest affinity being observed for GALR3, followed by GALR2; the putative fragment GALP (3rd-32nd) was also more effective than mature GALP (1st-60th) at displacing I-galanin.

Neuronal networks involving GALP-containing neurons

Galanin is widely distributed in the brain, but GALP-immunoreactive neuronal cell bodies are located in the hypothalamic ARC, being particularly dense in the medial posterior section of the nucleus. In the rat brain, GALP mRNA is expressed only in the ARC, with GALP-positive fibers projecting from this nucleus to several other hypothalamic nuclei, including the lateral septal nucleus, PVN, bed nucleus of the stria terminalis and MPA, as well as to the lateral hypothalamus (LH) around the fornix. On the basis of these results, at least two major neural pathways involving GALP have been proposed: one in which GALP-containing neurons project from the ARC to the PVN, and the other in which they project to the MPA, bed nucleus of the stria terminalis and lateral septal nucleus.

Fig. 1. Distribution of GALP-producing neurons in the hypothalamus. GALP-positive neurons are affected by leptin, which conveys satiety signals from the peripheral tissues, NPY and orexin. GALP regulates both orexigenic (NPY and/or orexin) and anorexigenic (POMC) pathways in the central nervous system.

With regard to the targets of GALP-containing neurons in rats, morphological studies have indicated that GALP-like-immunoreactive nerve fibers make direct contact with orexin- and MCH-like-immunoreactive neurons in the LH. At the ultrastructural level, GALP-immunoreactive axon terminals have been found to make synapses on orexin-immunoreactive cell bodies and dendritic processes in the LH. Previously studies reported that 3–12% of GALP positive neurons in the ARC also express a-MSH derived from POMC. These observations show that GALP-containing neurons introduce feeding and/or satiety signals. Furthermore, researchers have found that GALP-positive nerve fibers appear to make direct contact with tyrosine hydroxylase-containing neurons in the ARC, indicating that GALP may interact with dopaminergic neurons in this region. GALP-positive neurons have been shown to form circuits involving a number of neurons. Although galanin is co-expressed with many transmitters (monoamines and amino acids) and different peptides in neurons in various brain regions, it is yet to be reported that GALP-neurons express other neuropeptides or transmitters except a- MSH in the ARC, suggesting that GALP-expressing neurons are unique.

Effect of GALP on feeding behavior and energy metabolism

GALP is regulated by changes in metabolic status, such as during fasting and leptin administration, thus a role for GALP in feeding and metabolism was proposed. Currently, there is now considerable evidence demonstrating that central administration of GALP has potent effects on food intake and body weight in rodents, although these actions are complex and are both species- and time-dependent. GALP has dichotomous actions on energy balance in rat (transient hyperphagia followed by reduction of food intake and body weight), in contrast to acting as a reducing agent in both feeding behavior and body weight loss in mouse. Transient orexigenic actions of GALP are mediated by NPY and orexin pathway in the rat. The long-term anorectic and thermogenesis of GALP are mediated by proinflammatory pathway in rodents.

In rats, three pathways have been demonstrated to mediate the orexigenic effect of GALP: one through orexinergic neurons in the LH; one through NPY-expressing neurons in the DMH; and the third through POMC-expressing neurons in the ARC. c-Fos immunoreactivity is increased in orexin-immunoreactive neurons but not in MCH-immunoreactive neurons in the LH after intracerebroventricular injection of GALP. In addition, anti-orexin IgG markedly inhibits GALP induced hyperphagia. These results indicate that orexin-containing neurons in the LH are targeted by GALP, and that GALP induced hyperphagia is mediated through orexinergic neurons in the rat hypothalamus. Generally speaking, further elucidation of the functions of GALP is important for the discovery of therapeutic drugs, and for the treatment and prevention of obesity and related disorders.

References:

Lawrence C, Fraley G S. Galanin-like peptide (GALP) is a hypothalamic regulator of energy homeostasis and reproduction. Frontiers in Neuroendocrinology, 2011, 32(1):1-9.
Shioda S, et al. Galanin-like peptide: a key player in the homeostatic regulation of feeding and energy metabolism|[quest]|. International Journal of Obesity, 2011, 35(5):619.
Shiba K, et al. Galanin‐like peptide and the regulation of feeding behavior and energy metabolism. Febs Journal, 2010, 277(24):5006-5013.
Ito K, et al. Interactive effect of galanin-like peptide (GALP) and spontaneous exercise on energy metabolism. Peptides, 2013, 49(20):109-116.

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