Journal
CARDIOVASCULAR RESEARCH
Volume 97, Issue 1, Pages 97-105Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvs285
Keywords
Cardiomyocytes; Phospholipase C; U73122; K-2P channels; Cardiac action potential
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Funding
- Deutsche Forschungsgemeinschaft [DE1482/3-1, DE 1482/3-2, DA177/13-1, OL240/3-1, SFB 593/TPA4, SFB593/TPA12]
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The two-pore-domain potassium channel TASK-1 is robustly inhibited by the activation of receptors coupled to the G(q) subgroup of G-proteins, but the signal transduction pathway is still unclear. We have studied the mechanisms by which endothelin receptors inhibit the current carried by TASK-1 channels (I-TASK) in cardiomyocytes. Patch-clamp measurements were carried out in isolated rat cardiomyocytes. I-TASK was identified by extracellular acidification to pH 6.0 and by the application of the TASK-1 blockers A293 and A1899. Endothelin-1 completely inhibited I-TASK with an EC50 of 10 nM; this effect was mainly mediated by endothelin-A receptors. Application of 20 nM endothelin-1 caused a significant increase in action potential duration under control conditions; this was significantly reduced after pre-incubation of the cardiomyocytes with 200 nM A1899. The inhibition of I-TASK by endothelin-1 was not affected by inhibitors of protein kinase C or rho kinase, but was strongly reduced by U73122, an inhibitor of phospholipase C (PLC). The ability of endothelin-1 to activate PLC-mediated signalling pathways was examined in mammalian cells transfected with TASK-1 and the endothelin-A receptor using patch-clamp measurements and total internal reflection microscopy. U73122 prevented the inhibition of I-TASK by endothelin-1 and blocked PLC-mediated signalling, as verified with a fluorescent probe for phosphatidylinositol-(4,5)-bisphosphate hydrolysis. Our results show that I-TASK in rat cardiomyocytes is controlled by endothelin-1 and suggest that the inhibition of TASK-1 via endothelin receptors is mediated by the activation of PLC. The prolongation of the action potential observed with 20 nM endothelin-1 was mainly due to the inhibition of I-TASK.
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