A new orphan receptor involved in pulsatile growth hormone release

In all species studied to date, growth hormone (GH) is released episodicall y. Traditionally, the regulation of this process was considered to be media ted by two hypothalamic hormones, growth hormone-releasing hormone (GHRH) a nd somatostatin (sst). More recently, we identified a new orphan G-protein- coupled receptor that causes episodic GH release upon activation by synthet ic ligands. These ligands include the GH-releasing peptides (GHRPs) first d escribed by Bowers and their small molecule mimetics such as L-692,429 and MK-0677. Site-directed mutagenesis of this GH secretagogue receptor (GHS-R) has defined key amino acid residues essential for binding and activation b y the synthetic ligands. The GHS-R is not activated by GHRH or sst. It is e xpressed exclusively in the anterior pituitary lobe and central nervous sys tem and although this new receptor does not belong to any of the known fami lies of G-protein-coupled receptors, the GHS-R is highly conserved across s pecies. The Puffer fish homolog in common with the human GHS-R, is activate d by the structurally distinct ligands GHRP-6, MK-0677 and L-163, 540. Thus , the GHS-R ligand-binding pocket has apparently been conserved for at leas t 400 million years. Studies in humans suggest that production of an endoge nous ligand declines during aging. For example, chronic treatment with the synthetic ligand MK-0677 reverses the age-related physiological changes in the GH/IGF-I (insulin-like growth factor I) axis of 70-94 year old subjects . Based on the localization of expression of GHS-R in the brain, reduced pr oduction of the natural ligand might also be involved in age-associated cha nges in cognition, memory, mood and behavior.