Ghrelin

Overview: Ghrelin receptors (see Davenport et al., 2005) are activated by a 28 amino-acid peptide originally isolated from rat stomach, where it is cleaved from a 117 amino-acid precursor (ENSG00000157017). 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 (Matsumoto et al., 2001). Alternative splicing results in the formation of a second peptide, des-Gln¹⁴-ghrelin with equipotent biological activity (Hosoda et al., 2000). A unique post-translational modification (octanoylation of Ser³) occurs in both peptides, essential for full activity in binding to the ghrelin receptors in the hypothalamus and pituitary; and the release of growth hormone release from the pituitary (Kojima et al., 1999). Structure activity studies showed the first five N-terminal amino-acids to be the minimum required for binding (Bednarek et al., 2000), and receptor mutagenesis has indicated overlap of the ghrelin binding site with those for small molecule agonists and allosteric modulators of ghrelin function (Holst et al., 2009). In cell systems, the ghrelin receptor is constitutively active (Holst et al., 2004), 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 (Pantel et al., 2006).

Nomenclature	Ghrelin
Other names	GHS-R1a (Growth hormone secretagogue receptor type 1), growth hormone-releasing peptide receptor
Ensembl ID	ENSG00000121853
Principal transduction	Gq/11
Rank order of potency	Ghrelin = des-Gln-ghrelin (Matsumoto et al., 2001; Bedendi et al., 2003)
Selective antagonists	YIL781 (KB 11 nM) (Esler et al., 2007)
Probes	[125I-His9]-ghrelin (0.4 nM, Katugampola et al., 2001), [125I-Tyr4]-ghrelin (0.5 nM, Bedendi et al., 2003), [125I]-Tyr4-des-octanoyl (0.7 nM, Bedendi et al., 2003)

Des-octanoyl ghrelin has been shown to bind (as [¹²⁵I]-Tyr⁴-des-octanoyl ghrelin) and have effects in the cardiovascular system (Bedendi et al., 2003), 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-Trp^7,9,Leu¹¹]-substance P, pD₂ 8.3; Holst et al. 2003). TZP101, described as a ghrelin receptor agonist (pK_i 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 from the release of growth hormone (Fraser et al., 2008).

Glossary

Abbreviations:

TZP101

(4R,7S,10R,13R)-7-cyclopropyl-13-(4-fluorobenzyl)-3-oxa-6,9,12,15-tetraaza-4,9,10-trimethyl-4,5,6,7,10,12,13,15,16,17,18-undecahydro-1,2-benzocyclooctadecene-8,11,14-trione

YIL781

6-(4-fluorophenoxy)-3-([(3s)-1-isopropylpiperidin-3-yl]methyl)-2-methylquinazolin-4(3H)-one

Further Reading

Cao JM, Ong H, Chen C (2006). Effects of ghrelin and synthetic GH secretagogues on the cardiovascular system. Trends Endocrinol Metab17: 13–18.

Cummings DE (2006). Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav89: 71–84.

Davenport AP, Bonner TI, Foord SM, Harmar AJ, Neubig RR, Pin JP et al. (2005). International Union of Pharmacology. LVI. Ghrelin receptor nomenclature, distribution, and function. Pharmacol Rev57: 541–546.

De Vriese C, Delporte C (2007). Influence of ghrelin on food intake and energy homeostasis. Curr Opin Clin Nutr Metab Care10: 615–619.

Dezaki K, Sone H, Yada T (2008). Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis. Pharmacol Ther118: 239–249.

Garcia EA, Korbonits M (2006). Ghrelin and cardiovascular health. Curr Opin Pharmacol6: 142–147.

Hosoda H, Kojima M, Kangawa K (2006). Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci100: 398–410.

Kojima M, Kangawa K (2006). Drug insight: the functions of ghrelin and its potential as a multitherapeutic hormone. Nat Clin Pract Endocrinol Metab2: 80–88.

Leite-Moreira AF, Soares JB (2007). Physiological, pathological and potential therapeutic roles of ghrelin. Drug Discov Today12: 276–288.

Maguire JJ, Davenport AP (2005). Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci26: 448–454.

Olszewski PK, Schioth HB, Levine AS (2008). Ghrelin in the CNS: from hunger to a rewarding and memorable meal? Brain Res Rev58: 160–170.

Peeters TL (2006). Potential of ghrelin as a therapeutic approach for gastrointestinal motility disorders. Curr Opin Pharmacol6: 553–558.

Sanger GJ (2008). Motilin, ghrelin and related neuropeptides as targets for the treatment of GI diseases. Drug Discov Today13: 234–239.