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 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.
Tang
Bi
B
Department of Pulmonology, University Clinic of Internal Medicine, University Clinic Giessen, Giessen, Germany.
Li
Yingji
Y
Nagaraj
Chandran
C
Morty
Rory E
RE
Gabor
Sabine
S
Stacher
Elvira
E
Voswinckel
Robert
R
Weissmann
Norbert
N
Leithner
Katharina
K
Olschewski
Horst
H
Olschewski
Andrea
A
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
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