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

Endothelin (ET)-1 causes long-lasting vasoconstriction and vascular remodeling by interacting with specific G-protein–coupled recep-tors in pulmonary artery smooth muscle cells (PASMCs), and thus plays an important role in thepathophysiologyofpulmonaryarterial hypertension. The two-pore domain K1 channel, TASK-1, controls the restingmembrane 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 ETA receptors, phospholipase C, phosphatidylinositol 4,5-biphosphate, diacylgly-cerol, 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 K1 channel, TASK-1, has been identified in the ET-1–mediated depolarization in native hPASMC, and might represent a novel pathologic mechanism re-lated to pulmonary arterial hypertension