Ghrelin receptor in GtoPdb v.2025.3

Abstract

The ghrelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee for the Ghrelin receptor [19]) 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). A unique post-translational modification (octanoylation of Ser³, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [138] is essential for binding and activation of ghrelin receptors in all tissues, including the hypothalamus and pituitary [61]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [4], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [47]. The authorities in Japan have in 2020 approved the orally active agonist anamorelin, for the treatment of anorexia in cancer patients [130]. PF-05190457 is a small-molecule inverse agonist targeting the ghrelin receptor that has been progressed to phase I clinical trial for the treatment of alcoholism and has been demonstrated to decrease appetite [32]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [38, 71] inhibits ghrelin receptor-induced GH secretion and food intake [38]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [74]. In cell systems the ghrelin receptor is constitutively active [48], and this property is responsible for modulation of D₂ receptor signalling [20], and is attenuated by a naturally occurring mutation (A204E) that is associated with familial short stature [96].