Ghrelin

[Endogenous Growth-Hormone Releasing Peptide with Novel Regulatory Mechanism]

Small synthetic molecules called growth-hormone secretagogues (GHSs) stimulate the release of growth hormone (GH) from pituitary through a G-protein-coupled receptor (GHS-R) [Science, 260, 1640 (1993); Cell. Mol. Life Sci., 54, 1316 (1998)]. However, the specific endogenous ligand for this receptor has long been unidentified, therefore, this receptor is considered to be one of the orphan receptors. ]



Endogenous ligand for GHS-R is now identified as ghrelin with the following characteristics: 1) ghrelin is a 28-residue peptide with a n-octanoyl group at Ser³, 2) ghrelin stimulates GH-release from rat primary cultured pituitary cells in a dose-dependent manner (EC50 = 2.1 nM), and 3) ghrelin induces an increase of intracellular Ca²⁺ in GHS-R-expressing cells with EC50 value of 2.5 nM [Nature, 402, 656(1999)]. Although ghrelin and the known hypothalamic peptide, growth-hormone releasing factor, stimulate GH-release, there is distinction between these peptides both in GH secretion mechanism and in structural aspect. Octanoyl group attached on the side chain of Ser³ is essential for expressing activity. Rat and human peptide sequences are clarified to be mutually identical except for the amino acid substitutions at positions 11 and 12. Interestingly, major ghrelin-producing tissue is the stomach, and ghrelin immunoreactivity is found in healthy human blood. This fact may provide the new regulation mechanism for GH-release; ghrelin secreted from the stomach circulates in the blood stream to the pituitary where this peptide exerts a GH-releasing function. It is conceivable that ghrelin may have other functions in some tissues other than pituitary, because GHS-R is expressed in heart, lung, pancreas, intestine and adipose tissue.