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J. Biol. Chem., Vol. 280, Issue 2, 1490-1498, January 14, 2005

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Direct Voltage Control of Signaling via P2Y₁ and Other G_q-coupled Receptors^*

Juan Martinez-Pinna, Iman S. Gurung¶, Catherine Vial||, Catherine Leon**, Christian Gachet**, Richard J. Evans||, and Martyn P. Mahaut-Smith

From the Department of Physiology, University of Cambridge, Cambridge CB2 3EG, United Kingdom, ^||Department of Cell Physiology and Pharmacology, University of Leicester, Leicester, LE1 9HN, United Kingdom, and ^**INSERM U.311, EFS-Alsace 10, Strasbourg Cedex, 67065, France

Emerging evidence suggests that Ca²⁺ release evoked by certain G-protein-coupled receptors can be voltage-dependent; however, the relative contribution of different components of the signaling cascade to this response remains unclear. Using the electrically inexcitable megakaryocyte as a model system, we demonstrate that inositol 1,4,5-trisphosphate-dependent Ca²⁺ mobilization stimulated by several agonists acting via G_q-coupled receptors is potentiated by depolarization and that this effect is most pronounced for ADP. Voltage-dependent Ca²⁺ release was not induced by direct elevation of inositol 1,4,5-trisphosphate, by agents mimicking diacylglycerol actions, or by activation of phospholipase C-coupled receptors. The response to voltage did not require voltage-gated Ca²⁺ channels as it persisted in the presence of nifedipine and was only weakly affected by the holding potential. Strong predepolarizations failed to affect the voltage-dependent Ca²⁺ increase; thus, an alteration of G-protein subunit binding is also not involved. Megakaryocytes from P2Y₁^-/- mice lacked voltage-dependent Ca²⁺ release during the application of ADP but retained this response after stimulation of other G_q-coupled receptors. Although depolarization enhanced Ca²⁺ mobilization resulting from GTPS dialysis and to a lesser extent during or thimerosal, these effects all required the presence of P2Y₁ receptors. Taken together, the voltage dependence to Ca²⁺ release via G_q-coupled receptors is not due to control of G-proteins or down-stream signals but, rather, can be explained by a voltage sensitivity at the level of the receptor itself. This effect, which is particularly robust for P2Y₁ receptors, has wide-spread implications for cell signaling.

Received for publication, July 12, 2004 , and in revised form, November 3, 2004.

^* This work was supported by British Heart Foundation Grant PG/2000108, Medical Research Council Grants G9901465 and G0301031, and by the Royal Society and the Wellcome Trust. 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.

These authors contributed equally.

^¶ Recipient of a Gates Cambridge Trust Scholarship and an Overseas Research Student award.

To whom correspondence should be addressed. Tel.: 1223-333863; Fax: 1223-333840; E-mail: mpm11{at}cam.ac.uk.

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