TMEM16A is a Calcium-Activated Chloride Channel in Pulmonary Artery Smooth Muscle Cells

Abstract

Calcium-activated chloride channels (CaCCs) play pivotal roles in many physiological processes. In vascular smooth muscle, activation of these ion channels by agonist-induced Ca2+ release provokes membrane depolarisation, increased Ca2+ entry through L-type Ca2+ channels and ultimately vasoconstriction. The molecular identity of vascular CaCCs is not fully understood. Here we present evidence that TMEM16A (or Anoctamin1), a member of the transmembrane 16 (TMEM16) protein family forms CaCCs in pulmonary artery smooth muscle cells (PASMCs). Patch-clamp analysis in acutely isolated PASMCs revealed strongly outward rectifying Ca2+-activated Cl- currents which activated slowly at positive potentials and showed large deactivating tail currents upon repolarisation, very similar to heterologous TMEM16A currents (Caputo et al. (2008) Science 322, 590-594; Yang et al. (2008) Nature 455, 1210-1215; Schroeder et al. (2008) Cell 134, 1019-1029). High levels of TMEM16A mRNA were identified in rat pulmonary arteries and various other vascular smooth muscle cell types. Downregulation of TMEM16A gene expression in primary cultured PASMCs, with small interfering RNA, was accompanied by almost total loss of whole-cell CaCC currents. Our data suggest that TMEM16A forms calcium-activated chloride channels in rat pulmonary artery smooth muscle.