Ghrelin receptor


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 (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 [1]. Alternative splicing results in the formation of a second peptide, [des-Gln14]ghrelin with equipotent biological activity [2]. A unique post-translational modification (octanoylation of Ser3, catalysed by ghrelin Ο-acyltransferase (MBOAT4, Q96T53) [3] 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 [4]. Structure activity studies showed the first five N-terminal amino acids to be the minimum required for binding [5], and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function [6]. An endogenous antagonist and inverse agonist called Liver enriched antimicrobial peptide 2 (Leap2), expressed primarily in hepatocytes and in enterocytes of the proximal intestine [7,8] inhibits ghrelin receptor-induced GH secretion and food intake [7]. The secretion of Leap2 and ghrelin is inversely regulated under various metabolic conditions [9]. In cell systems, the ghrelin receptor is constitutively active [10], 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 [11].


  1. Matsumoto M, Hosoda H, Kitajima Y, et al. Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun 2001;287:142-6.
  2. Hosoda H, Kojima M, Matsuo H, et al. Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000;275:21995-2000.
  3. Yang J, Brown MS, Liang G, et al. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 2008;132:387-96.
  4. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999;402:656-60.
  5. Bednarek MA, Feighner SD, Pong SS, et al. Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 2000;43:4370-6.
  6. Holst B, Frimurer TM, Mokrosinski J, et al. Overlapping binding site for the endogenous agonist, small-molecule agonists, and ago-allosteric modulators on the ghrelin receptor. Mol Pharmacol 2009;75:44-59.
  7. Ge X, Yang H, Bednarek MA, et al. LEAP2 Is an Endogenous Antagonist of the Ghrelin Receptor. Cell Metab 2018;27:461-469.e6.
  8. M'Kadmi C, Cabral A, Barrile F, et al. N-Terminal Liver-Expressed Antimicrobial Peptide 2 (LEAP2) Region Exhibits Inverse Agonist Activity toward the Ghrelin Receptor. J Med Chem 2019;62:965-973.
  9. Mani BK, Puzziferri N, He Z, et al. LEAP2 changes with body mass and food intake in humans and mice. J Clin Invest 2019;129:3909-3923.
  10. Holst B, Holliday ND, Bach A, et al. Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem 2004;279:53806-17.
  11. Pantel J, Legendre M, Cabrol S, et al. Loss of constitutive activity of the growth hormone secretagogue receptor in familial short stature. J Clin Invest 2006;116:760-8.
Excerpt from IUPHAR/BPS Guide to Pharmacology
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