Structure-function studies on the new growth hormone-releasing peptide, ghrelin: Minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a

The recently discovered growth hormone secretagogue, ghrelin, is a potent a gonist at the human growth hormone secretagogue receptor la (hGHSR1a). To e lucidate structural features of this peptide necessary for efficient bindin g to and activation of the receptor, several analogues of ghrelin with vari ous aliphatic or aromatic groups in the side chain of residue 3, and severa l short peptides derived from ghrelin, were prepared and tested in a bindin g assay and in an assay measuring intracellular calcium elevation in HEK-29 3 cells expressing hGHSR1a. Bulky hydrophobic groups in the side chain of r esidue 3 turned out to be essential for maximum agonist activity. Also, sho rt peptides encompassing the first 4 or 5 residues of ghrelin were found to functionally activate hGHSR1a about as efficiently as the full-length ghre lin. Thus the entire sequence of ghrelin is not necessary for activity: the Gly-Ser-Ser(n-octanoyl)-Phe segment appears to constitute the "active core " required for agonist; potency at hGHSR1a.