Activity of Ca2+-Activated Cl− Channels Contributes to Regulating Receptor- and Store-Operated Ca2+ Entry in Human Pulmonary Artery Smooth Muscle Cells

PVRI Member Authors: Jason Yuan


Intracellular Ca2+ plays a fundamental role in regulating cell functions in pulmonary arterial smooth muscle cells (PASMCs). A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. [Ca2+]cyt is increased mainly by Ca2+ release from intracellular stores and Ca2+ influx through plasmalemmal Ca2+-permeable channels. Given the high concentration of intracellular Cl in PASMCs, Ca2+-activated Cl (ClCa) channels play an important role in regulating membrane potential and cell excitability of PASMCs. In this study, we examined whether activity of ClCa channels was involved in regulating [Ca2+]cytin human PASMCs via regulating receptor- (ROCE) and store- (SOCE) operated Ca2+ entry. The data demonstrated that an angiotensin II (100 nM)-mediated increase in [Ca2+]cyt via ROCE was markedly attenuated by the ClCa channel inhibitors, niflumic acid (100 µM), flufenamic acid (100 µM), and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (100 µM). The inhibition of ClCachannels by niflumic acid and flufenamic acid significantly reduced both transient and plateau phases of SOCE that was induced by passive depletion of Ca2+ from the sarcoplasmic reticulum by 10 µM cyclopiazonic acid. In addition, ROCE and SOCE were abolished by SKF-96365 (50 µM) and 2-aminoethyl diphenylborinate (100 µM), and were slightly decreased in the presence of diltiazem (10 µM). The electrophysiological and immunocytochemical data indicate that ClCacurrents were present and TMEM16A was functionally expressed in human PASMCs. The results from this study suggest that the function of ClCa channels, potentially formed by TMEM16A proteins, contributes to regulating [Ca2+]cyt by affecting ROCE and SOCE in human PASMCs.

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Cell Biochemistry and Metabolism, Differentiation and Proliferation, Structure and Function, interactions


Aya Yamamura, Hisao Yamamura, Amy Zeifman, Jason X.-J. Yuan

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Pulmonary Circulation Vol 1: No 2 cover image

June 2011

Pulmonary Circulation Vol 1: No 2

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