Published Time: Tue, 10 Mar 2026 12:27:20 GMT
The ghrelin receptor is activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor. 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. Alternative splicing results in the formation of a second peptide, des-Gln 14 ghrelin with equipotent biological activity. A unique post-translational modification (octanoylation of Ser 3, catalysed by ghrelin Ο-acyltransferase) 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. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding, and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine inhibits ghrelin receptor-induced GH secretion and food intake. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions. In cell systems, the ghrelin receptor is constitutively active, 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.
Excerpt from IUPHAR/BPS Guide to Pharmacology
