Buchumschlag

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

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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Hauptverfasser: Seyler, Claudia (VerfasserIn) , Duthil-Straub, Elvenn (VerfasserIn) , Zitron, Edgar (VerfasserIn) , Gierten, Jakob (VerfasserIn) , Scholz, Eberhard P. (VerfasserIn) , Fink, Rainer (VerfasserIn) , Karle, Christoph (VerfasserIn) , Becker, Rüdiger (VerfasserIn) , Katus, Hugo (VerfasserIn) , Thomas, Dierk (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 2012
In: British journal of pharmacology
Year: 2011, Jahrgang: 165, Heft: 5, Pages: 1467-1475
ISSN:1476-5381
DOI:10.1111/j.1476-5381.2011.01626.x
Online-Zugang:Verlag, Volltext: http://dx.doi.org/10.1111/j.1476-5381.2011.01626.x
Verlag, Volltext: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3372730/
Volltext
Verfasserangaben:C Seyler, E Duthil-Straub, E Zitron, J Gierten, EP Scholz, RHA Fink, CA Karle, R Becker, HA Katus, and D Thomas
Beschreibung
Zusammenfassung: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.
Beschreibung:Published online: 27 July 2011
2P ist im Titel tief- und das Pluszeichen hochgestellt
Gesehen am 18.07.2018
Beschreibung:Online Resource
ISSN:1476-5381
DOI:10.1111/j.1476-5381.2011.01626.x

Ähnliche Einträge