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Endothelin-1 Inhibits Background Two-Pore Domain Channel TASK-1 in Primary Human Pulmonary Artery Smooth Muscle Cells

¹ Department of Pulmonology, University Clinic of Internal Medicine, and ² Experimental Anesthesiology, University Clinic of Anesthesia and Intensive Care Medicine, ⁴ Department of Thoracic and Hyperbaric Surgery, University Clinic of Surgery, and ⁵ Institute of Pathology, Medical University of Graz, Graz, Austria; and ³ Department of Internal Medicine II, University Clinic Giessen, Giessen, Germany

Correspondence and requests for reprints should be addressed to Andrea Olschewski, M.D., Ph.D., Experimental Anesthesiology of the University Clinic of Anesthesia and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria. E-mail: andrea.olschewski{at}medunigraz.at

Endothelin (ET)-1 causes long-lasting vasoconstriction and vascular remodeling by interacting with specific G-protein–coupled receptors in pulmonary artery smooth muscle cells (PASMCs), and thus plays an important role in the pathophysiology of pulmonary arterial hypertension. The two-pore domain K⁺ channel, TASK-1, controls the resting membrane potential in human PASMCs (hPASMCs), and renders these cells sensitive to a variety of vasoactive factors, as previously shown. ET-1 may exert its vasoconstrictive effects in part by targeting TASK-1. To clarify this, we analyzed the ET-1 signaling pathway related to TASK-1 in primary hPASMCs. We employed the whole-cell patch–clamp technique combined with TASK-1 small interfering RNA (siRNA) in hPASMC and the isolated, perfused, and ventilated mouse lung model. We found that ET-1 depolarized primary hPASMCs by phosphorylating TASK-1 at clinically relevant concentrations. The ET sensitivity of TASK-1 required ET_A receptors, phospholipase C, phosphatidylinositol 4,5-biphosphate, diacylglycerol, and protein kinase C in primary hPASMCs. The ET-1 effect on membrane potential and TASK-1 was abrogated using TASK-1 siRNA. This is the first time that the background K⁺ channel, TASK-1, has been identified in the ET-1–mediated depolarization in native hPASMC, and might represent a novel pathologic mechanism related to pulmonary arterial hypertension.

Key Words: endothelin-1 • TASK-1 channel • membrane potential • pulmonary hypertension

CLINICAL RELEVANCE Endothelin-1 causes long-lasting vasoconstriction and vascular remodeling by interacting with specific G-protein-coupled receptors in human pulmonary artery smooth muscle cells. The inhibition of the background K+ channel TASK-1 by endothelin-1 might represent a novel pathologic mechanism related to pulmonary arterial hypertension.