TASK1 (K2P3.1) K+ channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation

• Verfasst von: Seyler, Claudia [VerfasserIn]
• Verfasst von: Duthil-Straub, Elvenn [VerfasserIn]
• Verfasst von: Zitron, Edgar [VerfasserIn]
• Verfasst von: Gierten, Jakob [VerfasserIn]
• Verfasst von: Scholz, Eberhard P. [VerfasserIn]
• Verfasst von: Fink, Rainer [VerfasserIn]
• Verfasst von: Karle, Christoph [VerfasserIn]
• Verfasst von: Becker, Rüdiger [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Thomas, Dierk [VerfasserIn]
• Titel: TASK1 (K2P3.1) K+ channel inhibition by endothelin-1 is mediated through Rho kinase-dependent phosphorylation
• Verf.angabe: C Seyler, E Duthil-Straub, E Zitron, J Gierten, EP Scholz, RHA Fink, CA Karle, R Becker, HA Katus, and D Thomas
• Jahr: 2012
• Jahr des Originals: 2011
• Umfang: 9 S.
• Fussnoten: Published online: 27 July 2011 ; 2P ist im Titel tief- und das Pluszeichen hochgestellt ; Gesehen am 18.07.2018
• Titel Quelle: Enthalten in: British journal of pharmacology
• Ort Quelle: Malden, MA : Wiley, 1946
• Jahr Quelle: 2012
• Band/Heft Quelle: 165(2012), 5, Seite 1467-1475
• ISSN Quelle: 1476-5381
• DOI: doi:10.1111/j.1476-5381.2011.01626.x
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1577733789

Abstract

BACKGROUND AND PURPOSE: TASK1 (K2P3.1) 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 IKN 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 ETA (IC50= 0.08 nM) and ETB (IC50= 0.23 nM) via Rho kinase signalling. TASK1 channels contain two putative Rho kinase phosphorylation sites, Ser336 and Ser393. Mutation of Ser393 rendered TASK1 channels insensitive to ETA- or ETB-mediated current inhibition. In contrast, removal of Ser336 selectively attenuated ETA-dependent TASK1 regulation without affecting the ETB pathway. CONCLUSIONS AND IMPLICATIONS: ET-1 regulated vascular TASK1 currents through ETA and ETB 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.