What is Ghrelin receptor?
Also called: GHS-R1a, GHSR, Growth hormone secretagogue receptor
The class A G protein-coupled receptor (GHS-R1a) for the stomach hormone ghrelin; it signals with high activity even when unbound and is the target of ipamorelin and the GHRPs.
By the APL Research Team · Updated
The ghrelin receptor, formally the growth hormone secretagogue receptor type 1a (GHS-R1a), is a G protein-coupled receptor of the pituitary and hypothalamus that triggers growth hormone release when activated. Its history runs backwards: the receptor was cloned in 1996 as the target of small synthetic growth hormone secretagogues, from pituitary and the arcuate and infundibular hypothalamus of swine and humans, while its natural ligand was still unknown [1]. Unlike the class B GHRH receptor, it belongs to class A, the rhodopsin-like family.
The endogenous ligand
The missing hormone was purified from rat stomach in 1999 and named ghrelin: a 28-residue peptide whose serine 3 carries an n-octanoyl ester, a modification essential for its GH-releasing activity [2]. Human and rat ghrelin differ at two positions [2]. The octanoyl group is attached by ghrelin O-acyltransferase (GOAT), a membrane enzyme whose mRNA is largely confined to stomach and intestine [3]. Without the acyl group, the peptide (des-acyl ghrelin) lacks the GH-releasing activity that defines the receptor's classic pharmacology [2].
Signalling and structure
Ghrelin and non-peptide secretagogues stimulate inositol phosphate turnover through the receptor, the signature of Gαq coupling [4]. The receptor is also unusually active with nothing bound. In transfected COS-7 and HEK293 cells it signalled strongly in the absence of ligand, whereas the closely related motilin receptor showed no such basal activity [4]. A modified substance P analogue reversed that basal signal completely, acting as a full inverse agonist with an EC50 of 5.2 nM [4].
The 2020 crystal structure, solved with an antagonist bound, found a ligand pocket split by a salt bridge between Glu124 and Arg283, and a hydrophobic, phenylalanine-rich gap between transmembrane helices 6 and 7. Mutagenesis suggested this crevice may engage ghrelin's octanoyl chain, offering a structural explanation for why the acyl group is needed [5].
Ligands used in research
| Ligand | Class | Note |
|---|---|---|
| Ghrelin (acyl) | Endogenous agonist | Ser3 octanoylation required for GH release [2] |
| Des-acyl ghrelin | Endogenous, non-acylated | Lacks GH-releasing activity [2] |
| GHRP-6 | Peptide agonist | Raised ACTH and cortisol as well as GH in swine [6] |
| Ipamorelin | Pentapeptide agonist, Aib-His-D-2-Nal-D-Phe-Lys-NH2 | EC50 1.3 nM for GH release from rat pituitary cells; ACTH and cortisol responses in swine no different from those after GHRH [6] |
| [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P | Inverse agonist | Suppresses constitutive signalling [4] |
Beyond GH release, ghrelin signalling has been linked to gut motility, gastric acid secretion, glucose metabolism, sleep–wake rhythm, reward behaviour and taste [7].
Points of confusion
- Two GH-releasing receptors. GHS-R1a (class A, Gαq, ligand from the stomach) and the GHRH receptor (class B, Gαs, ligand from the hypothalamus) are separate targets, which is why a GHRH analogue and a ghrelin-receptor agonist are often studied side by side, as in the CJC-1295 and ipamorelin blend. See growth hormone secretagogue for how the terms overlap.
- Basal signal is real signal. With high constitutive activity, a neutral antagonist and an inverse agonist give different results in the same assay, so the unstimulated baseline needs its own controls. The concentration–response design guide covers vehicle baselines and control wells.
- The acyl ester is part of the pharmacophore. Activity data for ghrelin are only meaningful if the peptide tested was actually octanoylated [2, 5].
References
- 1.Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996. PubMed 8688086
- 2.Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999. PubMed 10604470
- 3.Yang J, Brown MS, Liang G, et al. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008. PubMed 18267071
- 4.Holst B, Cygankiewicz A, Jensen TH, et al. High constitutive signaling of the ghrelin receptor--identification of a potent inverse agonist. Mol Endocrinol. 2003. PubMed 12907757
- 5.Shiimura Y, Horita S, Hamamoto A, et al. Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode. Nat Commun. 2020. PubMed 32814772
- 6.Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998. PubMed 9849822
- 7.Müller TD, Nogueiras R, Andermann ML, et al. Ghrelin. Mol Metab. 2015. PubMed 26042199