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

Tang B,Li Y,Nagaraj C,Morty RE,Gabor S,Stacher E,Voswinckel R,Weissmann N,Leithner K,Olschewski H,Olschewski A

doi

10.1165/rcmb.2008-0412OC

subject

Has Abstract

pub_date

2009-10-01 00:00:00

pages

476-83

issue

4

eissn

1044-1549

issn

1535-4989

pii

2008-0412OC

journal_volume

41

pub_type

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