Ghrelin and the GHRP Analogues, Pharmacology, Actions, and Promise for Hormone Replacement in the Elderly
Roy G. Smith, Ph.D.
Director, Huffington Center on Aging, and Professor, Departments of Molecular and Cellular Biology and Medicine, Baylor College of Medicine, Houston, TX
Aging is accompanied by alterations in the amplitude and frequency of release of hormones, neurotransmitters and neuropeptides. My laboratory is investigating the underlying mechanism of this decline of activity in the central nervous system (CNS) so that we can either, reverse, delay or prevent the age-dependent changes. In 1996, we characterized a new orphan G-protein coupled receptor, the growth hormone secretagogue receptor (GHS-R), based on high affinity binding of 35S-MK-0677 to membranes isolated from the pituitary gland and hypothalamus. The GHS-R was subsequently expression cloned from a pituitary cDNA library. Using in situ hybridization it was shown that the GHS-R was expressed in CNS regions that control hormone release from the pituitary gland, in regions enriched in dopaminergic and serotonergic neurons, as well as areas involved in neurogenesis and cognitive function. Activation of the GHS-R by the synthetic growth hormone releasing ligands MK-0677 and GHRP-6 increases the amplitude of pulsatile GH release in animals. The biological significance of the GHS-R to aging is exemplified by the demonstration that oral MK-0677, given once daily to frail elderly subjects, restores the age-related decline in GH pulse amplitude to that of adults in their twenties. This effect was sustained for at least 12 months and was accompanied by functional benefits such as increased muscle mass and modest improvements in strength. In the healthy elderly, administration of MK-0677 improves quality of sleep. The advantages of administering GHS-R ligands over GH or GH-releasing hormone (GHRH) injections are that: selected GHS-R ligands are efficacious when given orally; the increases in GH and IGF-1 remain within the physiological ranges and are subject to negative feedback; hence irrespective of dose, the GH/IGF-1 axis is protected from hyperstimulation. The physiological relevance of the GHS-R has now been confirmed by discovery of two natural ligands, ghrelin and adenosine. To determine how closely the natural ligands mimic the binding of the synthetic ligands, the ligands were compared using competitive binding assays with 35S-MK-0677 and activation of site directed mutants of the GHS-R. We will present data showing ghrelin, but not adenosine, is a competitive inhibitor of 35S-MK-0677 binding and that ghrelin occupies a different pocket to that occupied by GHRP-6 and MK-0677. Although administration of ghrelin mimics many of the in vivo effects of the synthetic GHS-R ligands, ghrelin appears to be less selective, and plasma levels of endogenous ghrelin are lower than would be anticipated if its action were solely through the GHS-R. Indeed, the in vivo data suggest that ghrelin acts on different GHS-R subtypes. We speculate that the cloned and well- characterized GHS-R is expressed exclusively in the CNS and pituitary gland, but that another subtype(s) are expressed in peripheral tissues. Ongoing studies are focused on determining whether activation of the GHS-R expressed in the CNS can prevent neurodegenration and memory loss during aging.
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