title: Endothelin-1 inhibits background two-pore domain channel TASK-1 in primary human pulmonary artery smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Pulmonology, University Clinic of Internal Medicine, University Clinic Giessen, Giessen, Germany.
authors.forename: Bi
authors.initials: B
authors.lastname: Tang
authors.forename: Yingji
authors.initials: Y
authors.lastname: Li
authors.forename: Chandran
authors.initials: C
authors.lastname: Nagaraj
authors.forename: Rory E
authors.initials: RE
authors.lastname: Morty
authors.forename: Sabine
authors.initials: S
authors.lastname: Gabor
authors.forename: Elvira
authors.initials: E
authors.lastname: Stacher
authors.forename: Robert
authors.initials: R
authors.lastname: Voswinckel
authors.forename: Norbert
authors.initials: N
authors.lastname: Weissmann
authors.forename: Katharina
authors.initials: K
authors.lastname: Leithner
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D004357:Drug Synergism; D063388:Endocannabinoids; D019332:Endothelin-1 / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010477:Perfusion; D010766:Phosphorylation / Q000187:drug effects; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011312:Pressure; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011651:Pulmonary Artery / Q000166:cytology* / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D019332:Endothelin-1; D009419:Nerve Tissue Proteins; D053284:Polyunsaturated Alkamides; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D011188:Potassium; C078814:anandamide