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Laboratory of Molecular Endocrinology, Department of Medicine, University of Santiago de Compostela and Research Area, Complejo Hospitalario Universitario de Santiago (CHUS), PO Box 563, E-15780 Santiago de Compostela, Spain
¹ Institut National de la Santé et de la Recherche Médicale, Unité 691, Collège de France, 75231 Paris, France

(Requests for offprints should be addressed to F F Casanueva; Email: endocrine{at}usc.es)

^* (M C Carreira and J P Camiña contributed equally to this work)

Ghrelin regulates GH secretion and energy homeostasis through the GH secretagogue receptor type-1a (GHS-R1a). This G-protein coupled receptor shows the peculiarity to transduce information provided not just by ghrelin as well as by adenosine through a supposed binding site different from the characterized ghrelin-binding pocket. Indeed, adenosine triggers intracellular calcium rise through a distinct signaling pathway to the one described for ghrelin, although it fails to stimulate GH secretion. Despite multiple active conformations of GHS-R1a, suggested as an explanation for a ligand-dependent activation of the downstream signaling, the concept of adenosine as agonist for GHS-R1a has been re-evaluated. The results revealed that calcium rise of both ghrelin and adenosine appears to be mediated by receptors that did not show the same sensitivity to protein kinase C (PKC) activity in GHS-R1a-transfected HEK 293 cells (HEK-GHS-R1a cells). The binding analyses showed the same number of adenosine-binding sites in both HEK 293 (B_max = 2.01 ± 0.15 fmol/cell) and HEK-GHS-R1a cells (B_max = 1.90 ± 0.11 fmol/cell). This binding was unaltered by different GHS-R1a antagonists. Western blot analysis showed a similar endogenous expression of endogenous adenosine receptor type-2b and -3 in both cell lines. The K_d values for adenosine were 1.78 µM in HEK 293 cells and 6.30 µM in HEK-GHS-R1a cells, pointing to a modification of agonist affinity induced by overexpression of the GHS-R1a. Additionally, adenosine failed to induce the GHS-R1a endocytosis, although it attenuates the ghrelin-induced GHS-R1a endocytosis. In conclusion, adenosine is not an agonist of the GHS-R1a and its action is mediated by the endogenous adenosine receptor type-2b and -3, which is able to partially use the intracellular signaling machinery of HEK-GHS-R1a cells.

This article has been cited by other articles:

				F. F. Casanueva, J. P. Camina, M. C. Carreira, Y. Pazos, J. L. Varga, and A. V. Schally Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a PNAS, December 23, 2008; 105(51): 20452 - 20457. [Abstract] [Full Text] [PDF]