Ghrelin receptor C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [3]) is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (GHRL, Q9UBU3). The human gene encoding the precursor peptide has 83% sequence homology to rat prepro-ghrelin, although the mature peptides from rat and human differ by only two amino acids [14]. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin (GHRL, Q9UBU3) with equipotent biological activity [9]. A unique post-translational modification (octanoylation of Ser3, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [22] occurs in both peptides, essential for full activity in binding to ghrelin receptors in the hypothalamus and pituitary, and for the release of growth hormone from the pituitary [11]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [2], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin (GHRL, Q9UBU3) function [7]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [5,12] inhibits ghrelin receptor-induced GH secretion and food intake [5]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [13]. In cell systems, the ghrelin receptor is constitutively active [8], but this is abolished by a naturally occurring mutation (A204E) that results in decreased cell surface receptor expression and is associated with familial short stature [18].
Receptors
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ghrelin receptor
C
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Concise Guide to PHARMACOLOGY citation:
Alexander SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors. Br J Pharmacol. 176 Suppl 1:S27-S156.
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[Des-octanoyl]ghrelin (GHRL, Q9UBU3) has been shown to bind (as [125I]Tyr4-des-octanoyl-ghrelin) and have effects in the cardiovascular system [1], which raises the possible existence of different receptor subtypes in peripheral tissues and the central nervous system. A potent inverse agonist has been identified ([D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P, pD2 8.3; [6]). Ulimorelin, described as a ghrelin receptor agonist (pKi 7.8 and pD2 7.5 at human recombinant ghrelin receptors), has been shown to stimulate ghrelin receptor mediated food intake and gastric emptying but not elicit release of growth hormone, or modify ghrelin stimulated growth hormone release, thus pharmacologically discriminating the orexigenic and gastrointestinal actions of ghrelin (GHRL, Q9UBU3) from the release of growth hormone [4]. Similar discrimination of ghrelin receptor mediated physiological functions can be obtained by activation of distinct signaling pathways [15]. A number of selective antagonists have been reported, including peptidomimetic [16] and non-peptide small molecules including GSK1614343 [19-21].