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Calcium-activated chloride channels (CaCCs) play important roles in several physiological processes. In vascular smooth muscle, activation of these ion channels by agonist-induced Ca(2+) release results in membrane depolarization and vasoconstriction. The molecular identity of vascular CaCCs is not fully defined. Here we present evidence that TMEM16A (or anoctamin 1), a member of the transmembrane 16 (TMEM16) protein family, forms CaCCs in pulmonary artery smooth muscle cells (PASMCs). Patch-clamp analysis in freshly isolated PASMCs revealed strongly outward-rectifying, slowly activating Ca(2+)-activated Cl(-) currents sharing a high degree of similarity with heterologous TMEM16A currents. TMEM16A mRNA was identified in rat and human pulmonary arteries and various other vascular smooth muscle cell types. Further analyses revealed that several TMEM16A splice variants were detected in rat PASMCs and that TMEM16F and TMEM16K were also expressed in these cells, while TMEM16B, TMEM16D and TMEM16E were all at least 50 times less abundantly expressed and the remaining TMEM16 family members were absent. Downregulation of TMEM16A gene expression in primary cultures of rat PASMCs, with small interfering RNAs, was accompanied by almost total loss of whole-cell CaCC currents. Based on these results, we propose that TMEM16A is the major constituent of the vascular calcium-activated chloride channel in rat pulmonary artery smooth muscle.

Original publication

DOI

10.1113/jphysiol.2010.189506

Type

Journal article

Journal

J Physiol

Publication Date

01/07/2010

Volume

588

Pages

2305 - 2314

Keywords

Algorithms, Animals, Anoctamin-1, Calcium, Cells, Cultured, Chloride Channels, Electrophysiology, Humans, Male, Myocytes, Smooth Muscle, Pulmonary Artery, RNA, Small Interfering, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, Solutions