GHSR

GHSR is the class A GPCR that mediates ghrelin's orexigenic, GH-secretory, and cardioprotective effects - and one of the few GPCRs with substantial constitutive (ligand-independent) activity. Its endogenous ligand ghrelin is the only known circulating hormone with an octanoyl modification essential for receptor binding. GHSR sits at the intersection of appetite, GH pulsatility, energy homeostasis, hippocampal memory, and cardiac protection. It is the target for macimorelin (approved for GH deficiency diagnosis) and several peptide GH secretagogues that have been through clinical trials. Every scaffold targeting appetite suppression, GH deficiency, or the ghrelin/GHSR axis routes through this card.

Receptor structure and signaling

GHSR (chromosome 3q26.31, 2 exons) produces two splice isoforms: GHSR-1a (366 aa, functional) and GHSR-1b (289 aa, 5 TM domains only, acts as dominant negative via heterodimerization). Ghrelin is a 28-aa peptide with an octanoyl group on Ser3 - this acylation is essential for binding (Ki ~1 nM vs. ~34 μM for unacylated ghrelin). The octanoyl chain occupies a hydrophobic pocket formed by ECL2 and TM7 residues (Phe286^{7.39}, Leu280^{7.33}), while the peptide backbone H-bonds Asp99^{2.61} and Gln120^{3.32}. Activation: Trp276^{6.48} toggle switch → TM6 outward rotation → Gq/11 docking → PLC-β → IP3/DAG → intracellular Ca²⁺ (EC₅₀ ~1 nM) and PKC. Secondary: Gi/o → ↓cAMP; β-arrestin → MAPK/ERK; PI3K/Akt in neurons. GHSR has ~50% constitutive activity - relevant to basal appetite and GH tone. GHSR-1a heterodimerizes with dopamine D2R, altering signaling in reward circuits. Expression is highest in pituitary, hypothalamic arcuate nucleus, and VTA; peripheral in stomach, heart, and adrenal.

Approved drugs and research scaffolds

Macimorelin (oral GHSR agonist) is FDA-approved for adult GH deficiency diagnosis. Ibutamoren (MK-677, oral GHS) showed sustained GH/IGF-1 elevation and muscle mass gains in clinical trials but is not approved and is WADA-prohibited. GHRP-6, GHRP-2, hexarelin, and pralmorelin (GHRP-2 derivative, approved in Japan for GH deficiency testing) are peptide GHSRs that established the pharmacophore: D-amino acid at position 1, Trp or aromatic at position 3, Lys-Trp core in GHRP-6. For peptide research, the tractable recipes are: GHRP-2/hexarelin analogs with D-amino acid and N-methylation substitutions for improved metabolic stability; inverse GHSR agonists (e.g., [D-Lys³]-GHRP-6) that suppress constitutive activity for appetite/obesity applications; and biased agonists that favor Gq/Ca²⁺ over β-arrestin to preserve GH pulse amplitude while blunting receptor internalization.