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Ghrelin is a growth-hormone-releasing acylated peptide from stomach


Small synthetic molecules called growth-hormone secretagogues (GHSs)1,2,3 stimulate the release of growth hormone (GH) from the pituitary4,5. They act through GHS-R, a G-protein-coupled receptor for which the ligand is unknown. Recent cloning of GHS-R6,7 strongly suggests that an endogenous ligand for the receptor does exist and that there is a mechanism for regulating GH release that is distinct from its regulation by hypothalamic growth-hormone-releasing hormone (GHRH)4,5. We now report the purification and identification in rat stomach of an endogenous ligand specific for GHS-R. The purified ligand is a peptide of 28 amino acids, in which the serine 3 residue is n-octanoylated. The acylated peptide specifically releases GH both in vivo and in vitro, and O-n-octanoylation at serine 3 is essential for the activity. We designate the GH-releasing peptide ‘ghrelin’ (ghre is the Proto-Indo-European root of the word ‘grow’). Human ghrelin is homologous to rat ghrelin apart from two amino acids. The occurrence of ghrelin in both rat and human indicates that GH release from the pituitary may be regulated not only by hypothalamic GHRH, but also by ghrelin.

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Figure 1: Gel filtration of Sephadex G-50 (fine) of SP-III fraction from 40 g rat stomach.
Figure 2: Identification of the n-octanoyl modification in ghrelin.
Figure 3: Dose–response relationships of [Ca2+]i change in CHO-GHSR62 cells, in the presence or absence of [D-Lys-3]-GHRP-6, a GHS-R-specific inhibitor.
Figure 4: Alignment of amino-acid sequences of human and rat prepro-ghrelin.
Figure 5: Effects of ghrelin on pituitary hormone secretion, in vitro and in vivo.
Figure 6: Expression studies of ghrelin.

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We thank R. Haruno for technical assistance; H. Kaiya and T. Maki for technical advice; and R. J. Adams for comments on the manuscript. This work was supported in part by Special Coordination Funds for Promoting Science and Technology from the Science and Technology Agency (Encouragement System of COE) (to H.M.), and a grant-in-aid for the Promotion of Fundamental Studies in Health Science from the Organization for Pharmaceutical Safety and Research of Japan (to K.K.).

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Correspondence to Masayasu Kojima.

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Kojima, M., Hosoda, H., Date, Y. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

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