Review
Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor

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Abstract

Growth hormone (GH) secretagogues (GHSs) are small synthetic molecules that act through a specific G-protein-coupled receptor (GPCR) called GHS-R. Until the recent identification of ‘ghrelin’ from rat and human stomachs, GHS-R was an orphan receptor (i.e. had no known natural ligand). Ghrelin is a 28-amino acid peptide with an essential n-octanoyl modification at Ser3. This peptide is found in the secretory granules of X/A-like cells, whose hormonal products and physiological functions have not been previously clarified. The discovery of ghrelin indicates that the release of GH from the pituitary might be regulated not only by hypothalamic GH-releasing hormone, but also by ghrelin derived from the stomach and hypothalamus.

Section snippets

GHS: what is a growth hormone secretagogue?

The field of GHS research grew out of studies conducted on opioid peptides during the 1970s. After the identification of enkephalins as the endogenous ligands for the morphine receptor in 1975, many opioid peptide derivatives were synthesized in an attempt to develop new anodynes that would be more potent and less addictive. In 1976, Cyril Y. Bowers of Tulane University (New Orleans, LA, USA) found that some opioid peptide derivatives had weak GH-releasing activity 7. After this observation,

Purification and identification of ghrelin, an endogenous ligand for the GHS-R

In recent years, searches for novel ligands using orphan GPCR-expressing cells have resulted in the discovery of several novel bioactive peptides, such as nociceptin/orphanin FQ (Refs 17, 18), orexins/hypocretins 19 and prolactin-releasing peptide 20. Indeed, orphan receptors represent important new tools for the discovery of novel bioactive molecules and for use in drug development 21.

Unlike other orphan GPCRs, GHS-R was known to bind artificial ligands, such as GHRP-6 or hexarelin, providing

Characteristics of the structures of ghrelin and its precursor

Ghrelin is the first known example of a bioactive peptide modified by an acyl acid. In fact, modification by n-octanoic acid is an unprecedented mechanism in mammals, although acyl modification has been seen in G proteins and receptors, which are conjugated to myristoyl acid (C14) or palmitoyl acid (C16) 23. Because the n-octanoyl modification of ghrelin is essential for its activity, the enzyme that catalyses the modification step should be important for the regulation of the activity of

Tissue distribution of ghrelin

Rat ghrelin mRNA, as shown by northern blot analysis, is expressed in the stomach. In situ hybridization and immunohistochemical analyses further indicated that ghrelin-containing cells are a distinct endocrine cell type found in the submucosal layer of the stomach. These cells, known as X/A-like cells, contain round, compact, electron-dense granules and are filled with ghrelin 27. Moreover, normal, adult human plasma samples contain 100–120 fmol ghrelin ml−1. These facts indicate that ghrelin

Physiological functions of ghrelin

Because GHSs, originally developed as activators of GH release, are agonists of the GHS-R, it was reasonable to expect that ghrelin, the endogenous ligand of GHS-R, possesses GH-releasing activity. In fact, ghrelin stimulates GH release from primary pituitary cells in a dose-dependent manner 6. This fact also indicates that ghrelin acts directly on the pituitary. This stimulation is specific; in vitro assays of pituitary cells have demonstrated that ghrelin does not stimulate the secretion of

Conclusion and prospects

In addition to the GHRH pathway, the first report of a GHS about 20 years ago introduced a new regulatory pathway for GH release. Since then, many potent GHSs have been developed, and the structure of the GHS-R has been identified. However, in spite of intensive research, until recently the identity of the endogenous ligand of the GHS-R remained elusive. The discovery of this peptide ligand, ghrelin, opens up a new area for clinical and basic GH research. The structure of ghrelin, and the

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