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Activity of Ca -activated Cl channels contributes to regulating receptor- and store-operated Ca entry in human pulmonary artery smooth muscle cells

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Title: Activity of Ca -activated Cl channels contributes to regulating receptor- and store-operated Ca entry in human pulmonary artery smooth muscle cells
Author(s): Yamamura, Aya; Yamamura, Hisao; Zeifman, Amy; Yuan, Jason X-J
Subject(s): angiotensin II Ca(2+) signaling Ca(2+) -activated Cl(-) current niflumic acid TMEM16A
Abstract: Intracellular Ca(2+) plays a fundamental role in regulating cell functions in pulmonary arterial smooth muscle cells (PASMCs). A rise in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)) triggers pulmonary vasoconstriction and stimulates PASMC proliferation. [Ca(2+)](cyt) is increased mainly by Ca(2+) release from intracellular stores and Ca(2+) influx through plasmalemmal Ca(2+)-permeable channels. Given the high concentration of intracellular Cl(-) in PASMCs, Ca(2+)-activated Cl(-)(Cl(Ca)) channels play an important role in regulating membrane potential and cell excitability of PASMCs. In this study, we examined whether activity of Cl(Ca) channels was involved in regulating [Ca(2+)](cyt) in human PASMCs via regulating receptor- (ROCE) and store- (SOCE) operated Ca(2+) entry. The data demonstrated that an angiotensin II (100 nM)-mediated increase in [Ca(2+)](cyt) via ROCE was markedly attenuated by the Cl(Ca) channel inhibitors, niflumic acid (100 muM), flufenamic acid (100 muM), and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (100 muM). The inhibition of Cl(Ca) channels by niflumic acid and flufenamic acid significantly reduced both transient and plateau phases of SOCE that was induced by passive depletion of Ca(2+) from the sarcoplasmic reticulum by 10 muM cyclopiazonic acid. In addition, ROCE and SOCE were abolished by SKF-96365 (50 muM) and 2-aminoethyl diphenylborinate (100 muM), and were slightly decreased in the presence of diltiazem (10 muM). The electrophysiological and immunocytochemical data indicate that Cl(Ca) currents were present and TMEM16A was functionally expressed in human PASMCs. The results from this study suggest that the function of Cl(Ca) channels, potentially formed by TMEM16A proteins, contributes to regulating [Ca(2+)](cyt) by affecting ROCE and SOCE in human PASMCs.
Issue Date: 2011-04
Publisher: Medknow Publications for the Pulmonary Vascular Research Institute (PVRI)
Citation Info: Yamamura, A., Yamamura, H., Zeifman, A., & Yuan, J. X. 2011. Activity of Ca -activated Cl channels contributes to regulating receptor- and store-operated Ca entry in human pulmonary artery smooth muscle cells. Pulmonary Circulation, 1(2): 269-279. DOI: 10.4103/2045-8932.83447
Type: Article
Description: The original version is available through Medknow Publications at DOI: 10.4103/2045-8932.83447
URI: http://hdl.handle.net/10027/8580
ISSN: 2045-8932
Sponsor: This work was supported, in part, by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health (HL066012 and HL098053 to JX-JY), Conflict of Interest: None declared.
Date Available in INDIGO: 2012-08-20
 

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