Na+ entry via TRPC6 causes Ca2+ entry via NCX reversal in ATP stimulated smooth muscle cells |
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Authors: | Lemos Virginia S Poburko Damon Liao Chiu-Hsiang Cole William C van Breemen Cornelis |
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Affiliation: | Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada V6T 1Z1. |
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Abstract: | Reversal of the Na+/Ca2+ -exchanger (NCX) has been shown to mediate Ca2+ influx during activation of G-protein linked receptors. Functional coupling between the reverse-mode NCX and the canonical transient receptor potential channels (TRPCs) has been proposed to mediate Ca2+ influx in HEK-293 cells overexpressing TRPC3. In this communication we present evidence for similar functional coupling of NCX to endogenously expressed TRPC6 in rat aorta smooth muscle cells. Selective inhibition of reverse-mode NCX with KB-R7943 and of non-selective cation-channels with SKF-96365 abolished Ca2+ influx in response to agonist stimulation (ATP). Expression of a dominant negative TRPC6 mutant also reduced the Ca2+ influx in proportion to its transfection efficiency. Calyculin A, which is known to disrupt the junctions of the plasma membrane and sarco/endoplasmic reticulum, increased global Na+ elevations and reduced stimulated Ca2+ influx. Together our data provide evidence that localized Na+ elevations are generated by TRPC6 and drive reversal of NCX to mediate Ca2+ influx. |
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Keywords: | Na+/Ca2+-exchanger TRPC6 channels Ca2+ influx Plasma membrane Sarcoplasmic reticulum Microdomains Na+ entry Smooth muscle cells Corona green Junctions |
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