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J. Biol. Chem., Vol. 280, Issue 44, 36824-36832, November 4, 2005

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Dopamine D2-like Receptors Are Expressed in Pancreatic Beta Cells and Mediate Inhibition of Insulin Secretion^*

Blanca Rubí1, Sanda Ljubicic, Shirin Pournourmohammadi, Stefania Carobbio, Mathieu Armanet, Clarissa Bartley, and Pierre Maechler2

From the Department of Cell Physiology and Metabolism, University Medical Center, and Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals, CH-1211 Geneva 4, Switzerland

Dopamine signaling is mediated by five cloned receptors, grouped into D1-like (D1 and D5) and D2-like (D2, D3 and D4) families. We identified by reverse transcription-PCR the presence of dopamine receptors from both families in INS-1E insulin-secreting cells as well as in rodent and human isolated islets. D2 receptor expression was confirmed by immunodetection revealing localization on insulin secretory granules of INS-1E and primary rodent and human beta cells. We then tested potential effects mediated by the identified receptors on beta cell function. Dopamine (10 µM) and the D2-like receptor agonist quinpirole (5 µM) inhibited glucose-stimulated insulin secretion tested in several models, i.e. INS-1E beta cells, fluorescence-activated cell-sorted primary rat beta cells, and pancreatic islets of rat, mouse, and human origin. Insulin exocytosis is controlled by metabolism coupled to cytosolic calcium changes. Measurements of glucose-induced mitochondrial hyperpolarization and ATP generation showed that dopamine and D2-like agonists did not inhibit glucose metabolism. On the other hand, dopamine decreased cell membrane depolarization as well as cytosolic calcium increases evoked by glucose stimulation in INS-1E beta cells. These results show for the first time that dopamine receptors are expressed in pancreatic beta cells. Dopamine inhibited glucose-stimulated insulin secretion, an effect that could be ascribed to D2-like receptors. Regarding the molecular mechanisms implicated in dopamine-mediated inhibition of insulin release, our results point to distal steps in metabolism-secretion coupling. Thus, the role played by dopamine in glucose homeostasis might involve dopamine receptors, expressed in pancreatic beta cells, modulating insulin release.

Received for publication, May 20, 2005 , and in revised form, August 17, 2005.

^* This work was supported by Swiss National Science Foundation Grants 3100-067023 and 3200B0-102134, the Max Cloetta Foundation (Zurich), and the Fondation Endocrinologie (Geneva). This study was part of the Geneva Programme for Metabolic Disorders. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed: Dept. of Cell Physiology and Metabolism, University Medical Centre, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland. E-mail: rubiweiss{at}yahoo.com. ² To whom correspondence may be addressed: Dept. of Cell Physiology and Metabolism, University Medical Centre, 1 rue Michel-Servet, CH-1211 Geneva 4, Switzerland. Tel.: 41-22-379-55-54; E-mail: Pierre.Maechler{at}medecine.unige.ch.

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