First Author | Martinez-Pinna J | Year | 2005 |
Journal | J Biol Chem | Volume | 280 |
Issue | 2 | Pages | 1490-8 |
PubMed ID | 15528188 | Mgi Jnum | J:96188 |
Mgi Id | MGI:3529654 | Doi | 10.1074/jbc.M407783200 |
Citation | Martinez-Pinna J, et al. (2005) Direct voltage control of signaling via P2Y1 and other Galphaq-coupled receptors. J Biol Chem 280(2):1490-8 |
abstractText | 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 Galphaq-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 Cgamma-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 betagamma 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 Galphaq-coupled receptors. Although depolarization enhanced Ca2+ mobilization resulting from GTPgammaS dialysis and to a lesser extent during AlF4- or thimerosal, these effects all required the presence of P2Y1 receptors. Taken together, the voltage dependence to Ca2+ release via Galphaq-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. |