Two identified transcript variants are expressed in several tissues and are evolutionary conserved in fish and swine. One transcript, 1a, excises an intron and encodes the functional protein; this protein is the receptor for the ghrelin ligand and defines a neuroendocrine pathway for growth hormone release. The second transcript (1b) retains the intron and does not function as a receptor for ghrelin; however, it may function to attenuate activity of isoform 1a.[6]
One important feature of GHS-R1a is that there is still some activity in the receptor even when it is not actively being stimulated. This is called constitutive activity, and it means that the receptor is always "on," unless acted on by an inverse agonist. This constitutive activity seems to provide a tonic signal required for the development of normal height, probably through an effect on the GH axis.[9] In fact, some genetic variations, or single nucleotide polymorphisms (SNPs), in growth hormone secretagogue receptor, have been found to be associated with hereditary obesity and others with hereditary short stature.[10] It was also found that, when GHS-R1A constitutive activity, was diminished, there were decreased levels of hunger-inducing hormone neuropeptide Y (NPY) as well as in food intake and body weight.[11][12]
It is well-characterized that activating the growth hormone secretagogue receptor with ghrelin induces an orexigenic state, or general feeling of hunger.[2] However, ghrelin may also play a role in behavioral reinforcement. Studies in animal models, found that food intake increased when ghrelin was specifically administered to just the ventral tegmental area (VTA), a brain area that uses dopamine signaling to reinforce behavior.[4] In fact, the more ghrelin administered, the more food the rodent consumed.[4] This is called a dose-dependent effect. Building on this, it was found that there are growth hormone secretagogue receptors in the VTA and that ghrelin acts on the VTA through these receptors.[4] Current studies, furthermore, suggest that the VTA may contain dimers of GHS-R1a and dopamine receptor type 2 (DRD2). If these two receptors do indeed form dimers, this would somehow link ghrelin signaling to dopaminergic signaling.[4]
The growth hormone secretagogue receptor may also be linked to learning and memory. First of all, the receptor is found in the hippocampus, the brain region responsible for long-term memory.[13] Second, it was found that specifically activating the receptor in just the hippocampus increased both long-term potentiation (LTP) and dendritic spine density, two cellular phenomena thought to be involved in learning.[4] Third, short-term calorie restriction, defined as a 30% reduction in caloric intake for two weeks, which naturally increases ghrelin levels and thus activates the receptor, was found to both increase both performance on spatial learning tasks as well as neurogenesis in the adult hippocampus.[13]
A range of selective ligands for the GHS-R receptor are now available and are being developed for several clinical applications. GHS-R agonists have appetite-stimulating and growth hormone-releasing effects, and are likely to be useful for the treatment of muscle wasting and frailty associated with old-age and degenerative diseases. On the other hand, GHS-R antagonists have anorectic effects and are likely to be useful for the treatment of obesity.
↑Wang W, Tao YX (2016). "Ghrelin Receptor Mutations and Human Obesity". Progress in Molecular Biology and Translational Science. 140: 131–50. doi:10.1016/bs.pmbts.2016.02.001. PMID27288828.
↑Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW (November 2003). "High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist". Molecular Endocrinology. 17 (11): 2201–10. doi:10.1210/me.2003-0069. PMID12907757.
↑Petersen PS, Woldbye DP, Madsen AN, Egerod KL, Jin C, Lang M, Rasmussen M, Beck-Sickinger AG, Holst B (November 2009). "In vivo characterization of high Basal signaling from the ghrelin receptor". Endocrinology. 150 (11): 4920–30. doi:10.1210/en.2008-1638. PMID19819980.
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