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(Circulation Research. 2007;101:1030.)
© 2007 American Heart Association, Inc.

Cellular Biology

Transient Receptor Potential Channel 6–Mediated, Localized Cytosolic [Na⁺] Transients Drive Na⁺/Ca²⁺ Exchanger–Mediated Ca²⁺ Entry in Purinergically Stimulated Aorta Smooth Muscle Cells

Damon Poburko, Chiu-Hsiang Liao, Virginia S. Lemos, Eric Lin, Yoshiaki Maruyama, William C. Cole, Cornelis van Breemen

From the Departments of Anesthesiology, Pharmacology & Therapeutics (D.P., C.-H.L., V.S.L., C.v.B.) and Cellular & Physiological Sciences (E.L.), University of British Columbia, Vancouver; Child & Family Research Institute (D.P., C.-H.L., V.S.L., C.v.B.), Vancouver; School of Kinesiology (E.L.), Simon Fraser University, Burnaby; and Smooth Muscle Research Group (Y.M., W.C.C.), Faculty of Medicine, University of Calgary, Alberta, Canada.

Correspondence to Cornelis van Breemen, Department of Anesthesiology, Pharmacology & Therapeutics, 2176 Health Sciences Mall, University of British Columbia, Vancouver, Canada, V6T 1Z1. E-mail breemen{at}interchange.ubc.ca

The Na⁺/Ca²⁺ exchanger (NCX) is increasingly recognized as a physiological mediator of Ca²⁺ influx and significantly contributes to salt-sensitive hypertension. We recently reported that Ca²⁺ influx by the NCX (1) is the primary mechanism of Ca²⁺ entry in purinergically stimulated rat aorta smooth muscle cells and (2) requires functional coupling with transient receptor potential channel 6 nonselective cation channels. Using the Na⁺ indicator CoroNa Green, we now directly observed and characterized the localized cytosolic [Na⁺] ([Na⁺]_i) elevations that have long been hypothesized to underlie physiological NCX reversal but that have never been directly shown. Stimulation of rat aorta smooth muscle cells caused both global and monotonic [Na⁺]_i elevations and localized [Na⁺]_i transients (LNats) at the cell periphery. Inhibition of nonselective cation channels with SKF-96365 (50 µmol/L) and 2-amino-4-phosphonobutyrate (75 µmol/L) reduced both global and localized [Na⁺]_i elevations in response to ATP (1 mmol/L). This effect was mimicked by expression of a dominant negative construct of transient receptor potential channel 6. Selective inhibition of NCX-mediated Ca²⁺ entry with KB-R7943 (10 µmol/L) enhanced the LNats, whereas the global cytosolic [Na⁺] signal was unaffected. Inhibition of mitochondrial Na⁺ uptake with CGP-37157 (10 µmol/L) increased both LNats and global cytosolic [Na⁺] elevations. These findings directly demonstrate NCX regulation by LNats, which are restricted to subsarcolemmal, cytoplasmic microdomains. Analysis of the LNats, which facilitate Ca²⁺ entry via NCX, suggests that mitochondria limit the cytosolic diffusion of LNats generated by agonist-mediated activation of transient receptor potential channel 6–containing channels.

Key Words: Na⁺/Ca²⁺ exchanger • localized [Na⁺] elevation • calcium • hypertension • mitochondria • CoroNa • ATP • TRPC

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