IDENTIFICATION OF A NEW G-PROTEIN-LINKED RECEPTOR FOR GROWTH-HORMONE SECRETAGOGUES

The potential application of small molecules in GH therapy has recentl y become a topic of increasing interest. The spiroindoline MK-0677, th e benzolactam L-692,429, and the peptides, GHRP-6 and hexarelin, have been shown to possess potent and selective GH-secretory activity in se veral species including human. Moreover, these synthetic GH secretagog ues act on a signal transduction pathway distinct from that of GHRH. A specific high affinity binding site in porcine and rat anterior pitui tary membranes that mediates the activity of these secretagogues has n ow been identified. The binding affinity of these structurally diverse secretagogues is tightly correlated with GH-secretory activity. The b inding is Mg2+-dependent, is inhibited by GTP-gamma-S, and is not disp laced by GHRH and somatostatin. The receptor is distinct from that for GHRH and has the properties of a new G-protein-coupled receptor. It i s speculated that these GH secretagogues mimic an unidentified natural hormone that regulates GH secretion in concert with GHRH and somatost atin.