Published online before print March 27, 2003, doi: 10.1161/01.RES.0000069216.80612.66
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Submitted on August 19, 2002
Revised on March 18, 2003
Accepted on March 18, 2003
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 ;
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.
* To whom correspondence should be addressed. 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+ (PCa/PNa 
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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