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TASK1 (K(2P)3.1) K(+) channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation

C Seyler1, E Duthil-Straub, E Zitron

  • 1Department of Cardiology, Medical University Hospital Heidelberg, Heidelberg, Germany.

British Journal of Pharmacology
|August 16, 2011
PubMed

Insights

Endothelin-1 inhibits TASK1 channels in human pulmonary artery smooth muscle cells via ET(A) and ET(B) receptors, mediated by Rho kinase. This pathway, involving direct channel phosphorylation, offers a potential therapeutic target for pulmonary arterial hypertension.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Pharmacology
  • Ion Channel Function

Background:

  • TASK1 (K(2P)3.1) channels are crucial for resting membrane potential in human pulmonary artery smooth muscle cells (hPASMC).
  • The endothelin-1 (ET-1) pathway, a target for pulmonary arterial hypertension (PAH) therapy, inhibits TASK1 currents in hPASMC, contributing to PAH pathophysiology.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which ET-1 inhibits TASK1 channels in hPASMC.

Main Methods:

  • Two-electrode and whole-cell patch clamp electrophysiology were employed to record TASK1 currents.
  • Experiments were conducted in hPASMC and Xenopus oocytes expressing TASK1 channels.

Main Results:

  • ET-1 inhibited TASK1 currents in hPASMC, an effect reduced by Rho kinase inhibition.
  • In oocytes, ET-1 inhibition of TASK1 was mediated by ET(A) and ET(B) receptors via Rho kinase signaling.
  • Phosphorylation sites Ser(336) and Ser(393) were identified; Ser(393) mutation abolished ET(A)/ET(B) inhibition, while Ser(336) removal selectively affected ET(A) pathway.

Conclusions:

  • ET-1 regulates vascular TASK1 currents through ET(A)/ET(B) receptors, activating Rho kinase and directly phosphorylating the channel.
  • The Rho kinase pathway presents a potential, specific therapeutic target for pulmonary arterial hypertension treatment.
Abstract

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