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(Circulation Research. 2003;92:888.)
© 2003 American Heart Association, Inc.

Cellular Biology

Crosstalk Between Voltage-Independent Ca²⁺ Channels and L-Type Ca²⁺ Channels in A7r5 Vascular Smooth Muscle Cells at Elevated Intracellular pH

Evidence for Functional Coupling Between L-Type Ca²⁺ Channels and a 2-APB–Sensitive Cation Channel

Michael Poteser, Ichiro Wakabayashi, Christian Rosker, Margot Teubl, Rainer Schindl, Nikolai M. Soldatov, Christoph Romanin, Klaus Groschner

From the Department of Pharmacology and Toxicology (M.P., C. Rosker, M.T., K.G.), Karl-Franzens-University Graz, Austria; Department of Hygiene and Preventive Medicine (I.W.), School of Medicine, Yamagata University, Yamagata, Japan; Department of Biophysics (R.S., C. Romanin), Johannes-Kepler-University Linz, Austria; and the National Institute of Aging (N.M.S.), National Institutes of Health, Baltimore, Md.

Correspondence to Dr Klaus Groschner, Dept of Pharmacology and Toxicology, Karl-Franzens-University Graz, A-8010 Graz, Austria. E-mail klaus.groschner{at}uni-graz.at

This study was designed to investigate the role of voltage-independent and voltage-dependent Ca²⁺ channels in the Ca²⁺ signaling associated with intracellular alkalinization in A7r5 vascular smooth muscle cells. Extracellular administration of ammonium chloride (20 mmol/L) resulted in elevation of intracellular pH and activation of a sustained Ca²⁺ entry that was inhibited by 2-amino-ethoxydiphenyl borate (2-APB, 200 µmol/L) but not by verapamil (10 µmol/L). Alkalosis-induced Ca²⁺ entry was mediated by a voltage-independent cation conductance that allowed permeation of Ca²⁺ (P_Ca/P_Na 6), and was associated with inhibition of L-type Ca²⁺ currents. Alkalosis-induced inhibition of L-type Ca²⁺ currents was dependent on the presence of extracellular Ca²⁺ and was prevented by expression of a dominant-negative mutant of calmodulin. In the absence of extracellular Ca²⁺, with Ba²⁺ or Na⁺ as charge carrier, intracellular alkalosis failed to inhibit but potentiated L-type Ca²⁺ channel currents. Inhibition of Ca²⁺ currents through voltage-independent cation channels by 2-APB prevented alkalosis-induced inhibition of L-type Ca²⁺ currents. Similarly, 2-APB prevented vasopressin-induced activation of nonselective cation channels and inhibition of L-type Ca²⁺ currents. We suggest the existence of a pH-controlled Ca²⁺ entry pathway that governs the activity of smooth muscle L-type Ca²⁺ channels due to control of Ca²⁺/calmodulin-dependent negative feedback regulation. This Ca²⁺ entry pathway exhibits striking similarity with the pathway activated by stimulation of phospholipase-C–coupled receptors, and may involve a similar type of cation channel. We demonstrate for the first time the tight functional coupling between these voltage-independent Ca²⁺ channels and classical voltage-gated L-type Ca²⁺ channels.

Key Words: intracellular pH • Ca²⁺ channels • nonselective cation channels • 2-APB • smooth muscle

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