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AIMS: The two-pore-domain potassium channel TASK-1 is robustly inhibited by the activation of receptors coupled to the Gα(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. METHODS AND RESULTS: 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 EC(50) 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. CONCLUSION: 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).

Original publication

DOI

10.1093/cvr/cvs285

Type

Journal article

Journal

Cardiovasc Res

Publication Date

01/01/2013

Volume

97

Pages

97 - 105

Keywords

Action Potentials, Animals, CHO Cells, Cricetinae, Cricetulus, Endothelin-1, Enzyme Activation, Enzyme Inhibitors, Hydrogen-Ion Concentration, Hydrolysis, Ion Channel Gating, Kinetics, Microscopy, Fluorescence, Microscopy, Interference, Myocytes, Cardiac, Patch-Clamp Techniques, Phosphatidylinositol 4,5-Diphosphate, Potassium Channel Blockers, Potassium Channels, Tandem Pore Domain, Rats, Receptor, Endothelin A, Signal Transduction, Transfection, Type C Phospholipases