1. TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation.
- Author
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Seyler C, Duthil-Straub E, Zitron E, Gierten J, Scholz EP, Fink RH, Karle CA, Becker R, Katus HA, and Thomas D
- Subjects
- Animals, Cells, Cultured, Female, GTP Phosphohydrolases metabolism, Humans, Hypertension, Pulmonary genetics, Hypertension, Pulmonary metabolism, Hypertension, Pulmonary physiopathology, Membrane Potentials genetics, Membrane Potentials physiology, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular physiology, Mutation, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle physiology, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Phosphorylation, Potassium Channels, Tandem Pore Domain genetics, Potassium Channels, Tandem Pore Domain metabolism, Pulmonary Artery metabolism, Pulmonary Artery physiology, Receptor, Endothelin A metabolism, Receptor, Endothelin B metabolism, Signal Transduction, Vasoconstriction genetics, Vasoconstriction physiology, Xenopus laevis, rho-Associated Kinases antagonists & inhibitors, Endothelin-1 metabolism, Nerve Tissue Proteins antagonists & inhibitors, Potassium Channels, Tandem Pore Domain antagonists & inhibitors, rho-Associated Kinases metabolism
- Abstract
Background and Purpose: TASK1 (K(2P)3.1) two-pore-domain K(+) channels contribute substantially to the resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC), modulating vascular tone and diameter. The endothelin-1 (ET-1) pathway mediates vasoconstriction and is an established target of pulmonary arterial hypertension (PAH) therapy. ET-1-mediated inhibition of TASK1 currents in hPASMC is implicated in the pathophysiology of PAH. This study was designed to elucidate molecular mechanisms underlying inhibition of TASK1 channels by ET-1., Experimental Approach: Two-electrode voltage clamp and whole-cell patch clamp electrophysiology was used to record TASK1 currents from hPASMC and Xenopus oocytes., Key Results: ET-1 inhibited TASK1-mediated I(KN) currents in hPASMC, an effect attenuated by Rho kinase inhibition with Y-27632. In Xenopus oocytes, TASK1 current reduction by ET-1 was mediated by endothelin receptors ET(A) (IC(50) = 0.08 nM) and ET(B) (IC(50) = 0.23 nM) via Rho kinase signalling. TASK1 channels contain two putative Rho kinase phosphorylation sites, Ser(336) and Ser(393) . Mutation of Ser(393) rendered TASK1 channels insensitive to ET(A) - or ET(B)-mediated current inhibition. In contrast, removal of Ser(336) selectively attenuated ET(A) -dependent TASK1 regulation without affecting the ET(B) pathway., Conclusions and Implications: ET-1 regulated vascular TASK1 currents through ET(A) and ET(B) receptors mediated by downstream activation of Rho kinase and direct channel phosphorylation. The Rho kinase pathway in PASMC may provide a more specific therapeutic target in pulmonary arterial hypertension treatment., (© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.)
- Published
- 2012
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