Role of the Growth Hormone Secretagogue Receptor in the Central Nervous System

Abstract

Aging is accompanied by a decline in the amplitude of the release of hormones, neurotransmitters and neuropeptides. These changes are associated with alterations in metabolism resulting in increases in deposition of visceral fat at the expense of muscle. My laboratory is investigating the underlying mechanism of this declining activity of the central nervous system (CNS) and related metabolic alterations. Our objective is to reverse, delay or prevent these changes. We focused on the age-dependent attenuation of pulsatile growth hormone release as a paradigm because of the known anabolic effects of GH. Accordingly, we characterized and expression cloned a new orphan G-protein coupled receptor, the growth hormone secretagogue receptor (GHS-R), which regulates the amplitude of GH pulsatility. In situ hybridization showed that the GHS-R was expressed in CNS regions controlling hormone release from the pituitary gland and in regions enriched in dopaminergic and serotonergic neurons, all of which are known to be involved in metabolism as well as in control of appetite. The physiological relevance of the GHS-R has been confirmed by identification of two natural ligands, ghrelin and adenosine. Interestingly, these endogenous ligands are reported to increase appetite. Besides rejuvenating the GH axis, the GHS-R ligands activate a subset of NPY neurons, and it has been speculated that this property explains the stimulation of feeding behavior. To determine how closely ghrelin mimics the properties of MK-0677, the synthetic ligand for GHS-R, we constructed site-directed mutants of the GHS-R and compared their activity when treated with the two ligands. The results showed that ghrelin occupies a different activation pocket than that occupied by MK-0677. Although administration of ghrelin mimics many of the in vivo effects of MK-0677, ghrelin appears to be less GHS-R selective, suggesting that ghrelin may act through a GHS-R subtype. Studies with GHS-R −/− and ghrelin −/− mice will establish whether ghrelin and MK-0677 act on different GHS-R subtypes and whether the metabolic and orexigenic effects are mediated through different signaling pathways.