Growth hormone releasing substances: Types and their receptors

A series of structurally diverse growth hormone (GH) releasing substances h ave been synthesized that are distinct from the naturally occurring GH rele asing hormone (GHRH). These synthetic molecules range from the family of GH releasing peptides and mimetics such as MK-0677. The physiological importa nce of these molecules and their receptor is exemplified by studies in the elderly. For example, when MK-0677 was administered chronically to 70- to 9 0-year-old subjects, once daily, the age-related reduced amplitude of GH pu lses was reversed to that of the physiological profile typical of young adu lts. In 1996, the synthesis of S-35-MK-0677 was reported and used as a liga nd to characterize a common receptor (GH secretagogue receptor [GHS-R]) for the GH releasing substances. The GHS-R is distinct from the GHRH receptor. Subsequently, the GHS-R gene was cloned and shown to encode a unique G-pro tein coupled receptor with a deduced protein sequence that was 96% identica l in human and rat. Because of the physiological importance of the GHS-R, a search for family members (FMs) was initiated and its molecular evolution investigated. Three FMs GPR38, GPR39 and FM3 were isolated from human genom ic libraries. To accelerate the identification of other FMs, a vertebrate o rganism with a compact genome distant in evolutionary terms from hu ma ns w as exploited. The pufferfish (Spheroides nephelus) genome provides an ideal model for the discovery of human genes. Three distinct full-length clones encoding proteins of significant sequence identity to the human GHS-R were cloned from the pufferfish. Remarkably, the pufferfish gene with highest se quence homology to the human receptor was activated by the hexapeptide and non-peptide ligands. These intriguing results show that the structure and f unction of the ligand binding pocket of the human GHS-R has been highly con served in evolution (similar to 400 million years) and strongly suggests th at an endogenous natural ligand has been conserved. This new information is consistent with a natural ligand for the GHS-R playing a fundamentally imp ortant and conserved role in physiology. Copyright (C) 1999 S.Karger AG, Ba sel.