Published online before print March 30, 2006, doi: 10.1161/01.RES.0000219677.12988.e9
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© 2006 American Heart Association, Inc.
Cellular Biology |
Impact of TASK-1 in Human Pulmonary Artery Smooth Muscle Cells
From the Department of Anaesthesiology (A.O., M.E.B.), Intensive Care Medicine, Medical University Graz, Austria; University of Giessen Lung Center (A.O., Y.L., B.T., J.H., B.E., R.E.M., W.S.), Medical Clinic II/V; and Department of Pathology (R.M.B., J.W., G.K.), Justus-Liebig University Giessen, Germany; Minneapolis VA Medical Center and University of Minnesota (E.K.W.); Department of Cardio-Thoracic Surgery (W.K.), Vienna University Hospital, Austria; and Division of Pulmonology (H.O.), Medical University Graz, Austria.
Correspondence to Andrea Olschewski, Department of Anaesthesiology, Intensive Care Medicine, Medical University Graz, Auenbruggerplatz 29, A-8029 Graz, Austria. E-mail andrea.olschewski{at}physiologie.med.uni-giessen.de
The excitability of pulmonary artery smooth muscle cells (PASMC) is regulated by potassium (K+) conductances. Although studies suggest that background K+ currents carried by 2-pore domain K+ channels are important regulators of resting membrane potential in PASMC, their role in human PASMC is unknown. Our study tested the hypothesis that TASK-1 leak K+ channels contribute to the K+ current and resting membrane potential in human PASMC. We used the whole-cell patch-clamp technique and TASK-1 small interfering RNA (siRNA). Noninactivating K+ current performed by TASK-1 K+ channels were identified by current characteristics and inhibition by anandamide and acidosis (pH 6.3), each resulting in significant membrane depolarization. Moreover, we showed that TASK-1 is blocked by moderate hypoxia and activated by treprostinil at clinically relevant concentrations. This is mediated via protein kinase A (PKA)-dependent phosphorylation of TASK-1. To further confirm the role of TASK-1 channels in regulation of resting membrane potential, we knocked down TASK-1 expression using TASK-1 siRNA. The knockdown of TASK-1 was reflected by a significant depolarization of resting membrane potential. Treatment of human PASMC with TASK-1 siRNA resulted in loss of sensitivity to anandamide, acidosis, alkalosis, hypoxia, and treprostinil. These results suggest that (1) TASK-1 is expressed in human PASMC; (2) TASK-1 is hypoxia-sensitive and controls the resting membrane potential, thus implicating an important role for TASK-1 K+ channels in the regulation of pulmonary vascular tone; and (3) treprostinil activates TASK-1 at clinically relevant concentrations via PKA, which might represent an important mechanism underlying the vasorelaxing properties of prostanoids and their beneficial effect in vivo.
Key Words: pulmonary circulation • potassium channels • TASK-1 • treprostinil • hypoxic pulmonary vasoconstriction
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