Paper

Heterogeneity of Ghrelin/Growth Hormone Secretagogue Receptors
Toward the Understanding of the Molecular Identity of Novel Ghrelin/GHS Receptors
Giampiero Muccioli^a, Alessandra Baragli^a, Riccarda Granata^b, Mauro Papotti^c, Ezio Ghigo<sup>b

a</sup>Division of Pharmacology, Department of Anatomy, Pharmacology and Forensic Medicine,
^bDivision of Endocrinology and Metabolism, Department of Internal Medicine, and
^cDivision of Pathology, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy

Address of Corresponding Author

Neuroendocrinology 2007;86:147-164 (DOI: 10.1159/000105141)

  Key Words

• Ghrelin
• Growth hormone secretagogues
• Receptor types

  Abstract

Ghrelin is a gastric polypeptide displaying strong GH-releasing activity by activation of the type 1a GH secretagogue receptor (GHS-R1a) located in the hypothalamus-pituitary axis. GHS-R1a is a G-protein-coupled receptor that, upon the binding of ghrelin or synthetic peptidyl and non-peptidyl ghrelin-mimetic agents known as GHS, preferentially couples to G_q, ultimately leading to increased intracellular calcium content. Beside the potent GH-releasing action, ghrelin and GHS influence food intake, gut motility, sleep, memory and behavior, glucose and lipid metabolism, cardiovascular performances, cell proliferation, immunological responses and reproduction. A growing body of evidence suggests that the cloned GHS-R1a alone cannot be the responsible for all these effects. The cloned GHS-R1b splice variant is apparently non-ghrelin/GHS-responsive, despite demonstration of expression in neoplastic tissues responsive to ghrelin not expressing GHS-R1a; GHS-R1a homologues sensitive to ghrelin are capable of interaction with GHS-R1b, forming heterodimeric species. Furthermore, GHS-R1a-deficient mice do not show evident abnormalities in growth and diet-induced obesity, suggesting the involvement of another receptor. Additional evidence of the existence of another receptor is that ghrelin and GHS do not always share the same biological activities and activate a variety of intracellular signalling systems besides G_q. The biological actions on the heart, adipose tissue, pancreas, cancer cells and brain shared by ghrelin and the non-acylated form of ghrelin (des-octanoyl ghrelin), which does not bind GHS-R1a, represent the best evidence for the existence of a still unknown, functionally active binding site for this family of molecules. Finally, located in the heart and blood vessels is the scavenger receptor CD36, involved in the endocytosis of the pro-atherogenic oxidized low-density lipoproteins, which is a pharmacologically and structurally distinct receptor for peptidyl GHS and not for ghrelin. This review highlights the most recently discovered features of GHS-R1a and the emerging evidence for a novel group of receptors that are not of the GHS1a type; these appear involved in the transduction of the multiple levels of information provided by GHS and ghrelin.

Copyright © 2007 S. Karger AG, Basel

  Author Contacts

Ezio Ghigo
Division of Endocrinology and Metabolism
Department of Internal Medicine, University of Turin
Corso Dogliotti 14, IT-10126 Turin (Italy)
Tel. +39 011 633 4317, Fax +39 011 664 7421, E-Mail ezio.ghigo@unito.it

  Article Information

Received: January 5, 2007
Accepted after revision: May 21, 2007
Published online: July 2, 2007
Number of Print Pages : 18
Number of Figures : 0, Number of Tables : 1, Number of References : 234