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...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
2012
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| In: |
British journal of pharmacology
Year: 2011, Volume: 165, Issue: 5, Pages: 1467-1475 |
| ISSN: | 1476-5381 |
| DOI: | 10.1111/j.1476-5381.2011.01626.x |
| Online Access: | 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/ 
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| Author Notes: | C Seyler, E Duthil-Straub, E Zitron, J Gierten, EP Scholz, RHA Fink, CA Karle, R Becker, HA Katus, and D Thomas |
| Summary: | 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. |
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| Item Description: | Published online: 27 July 2011 2P ist im Titel tief- und das Pluszeichen hochgestellt Gesehen am 18.07.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1476-5381 |
| DOI: | 10.1111/j.1476-5381.2011.01626.x |