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CELLULAR AND MOLECULAR

Potentiation of P2X1 ATP-Gated Currents by 5-Hydroxytryptamine 2A Receptors Involves Diacylglycerol-Dependent Kinases and Intracellular Calcium

Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada

Postsynaptic P2X1 ATP-gated channels are expressed in smooth muscle cells of the vascular and genitourinary systems, where they mediate desensitizing neurogenic contractions. Using the model of the isolated rat tail artery, we show that the vasoactive mediator 5-hydroxytryptamine (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 (also named PKCµ) downstream of phospholipase C. Other major kinases like Ca²⁺/calmodulin kinase II, protein kinase A, mitogen-activated protein kinases, and tyrosine kinases were found not to be involved. Moreover, we report that buffering intracellular Ca²⁺ ions with the chelator 1,2-bis(O-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (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 phorbol ester 12-myristate 13-acetate. 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.

Address correspondence to: Dr. Philippe Séguéla, Montreal Neurological Institute, 3801 University, Office 778, Montreal, QC, Canada H3A 2B4. E-mail: philippe.seguela{at}mcgill.ca