Ghrelin is a new acylated peptide which is mainly produced by the stomach, but it is also present in the hypothalamus and in several other tissues. This endogenous growth hormone secretagogue (GHS) was discovered by reverse pharmacology, as initially a group of synthetic GH-releasing compounds were produced, leading to the isolation of an orphan receptor and, finally, to its endogenous ligand. Ghrelin binds to an active receptor GHSR-1a to increase GH release and food intake. It is still unknown how hypothalamic and circulating ghrelin are involved in the control of GH release. Endogenous ghrelin might act to amplify the basic pattern of GH secretion, optimizing somatotroph responsiveness to GHRH. It may activate multiple interdependent intracellular pathways at the somatotroph, involving PKC, PKA and extracellular calcium systems. However, as ghrelin has a greater ability to release GH in vivo, its main site of action is the hypothalamus. In the current review we summarize the available data on the: a) discovery of this peptide ; b) mechanisms of action of GHS and ghrelin and possible physiological role on GH modulation and; c) regulation of GH release in man after iv administration of these peptides.
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