Growth Hormone Secretagogue Receptor (GHS-R1a)

GHS-R1a is a class A G protein-coupled receptor signalling predominantly through Gq, activating phospholipase C to generate inositol trisphosphate and mobilise intracellular calcium, which in the somatotroph triggers growth hormone exocytosis. Its endogenous ligand is acylated ghrelin, and the octanoyl group is required for activation. The gene also produces a truncated splice variant, GHS-R1b, which does not signal and appears to modulate trafficking of the full-length receptor. The receptor's most distinctive property is very high constitutive activity, signalling at a substantial fraction of its maximum with no ligand bound at all.

It was cloned in 1996 as the target of synthetic secretagogues, three years before its natural ligand was found, an unusual inversion of the normal order of discovery. It is expressed on pituitary somatotrophs, on NPY and AgRP neurons of the hypothalamic arcuate nucleus and on vagal afferents. The clinical weight of its constitutive activity is shown by a rare familial short stature syndrome in which a receptor mutation abolishes basal signalling while leaving ghrelin binding intact.

That property changes how the receptor should be targeted. Blocking it usefully may require an inverse agonist that reduces basal signalling rather than a neutral antagonist that only displaces ligand. It also explains why the appetite and growth hormone arms of the response are hard to dissociate, since both lie downstream of the same receptor in different cell populations.

The claim to distrust is selectivity. Ghrelin mimetics also raise prolactin and, to a variable degree, ACTH and cortisol, so describing a given releasing peptide as selective for growth hormone overstates what the receptor pharmacology supports. A related confusion is treating this receptor as the target of GHRH analogues, which act at an entirely separate class B receptor.