Received for publication May 4, 2005.
Revised June 13, 2005.
Accepted for publication June 13, 2005.

Potentiation of P2X1 ATP-gated currents by 5-HT2A receptors involves diacylglycerol-dependent kinases and intracellular calcium

Abstract

Postsynaptic P2X1 ATP-gated channels are expressed in smooth muscle cells of the vascular and genito-urinary systems, where they mediate desensitizing neurogenic contractions. Using the model of the isolated rat tail artery, we show that the vasoactive mediator 5-HT, via the 5 HT_2A metabotropic receptor, regulates the desensitization kinetics of P2X1 responses by increasing their rate of recovery. Reconstituting the potentiation of P2X1 ATP-gated currents by 5 HT_2A receptors in the Xenopus oocyte expression system, we provide evidence that this modulation depends on the activation of novel protein kinase C isoforms and protein kinase D (PKCµ) downstream of phospholipase C. Other major kinases like Ca²⁺/calmodulin kinase II, protein kinase A, MAP kinases and tyrosine kinases, were found not to be involved. Moreover, we report that buffering intracellular Ca²⁺ ions with the chelator BAPTA decreases the rate of recovery of P2X1 responses and increases their sensitivity to potentiation by 5-HT_2A receptors or by the diacylglycerol analog PMA. We conclude that intracellular Ca²⁺ and a subset of diacylglycerol-dependent protein kinases regulate the activity of P2X1 receptor-channels by modulating their recovery from desensitization.

Key words: P2X, protein kinase, purinergic, purinoceptor, serotonin, smooth muscle

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