The inhibition of the potassium channel TASK-1 in rat cardiac muscle by endothelin-1 is mediated by phospholipase C
| Autor: | Andrea Hetzel, Konstantin Wemhöner, Vijay Renigunta, Dominik Oliver, Günter Schlichthörl, Niels Decher, Jürgen Daut, Moritz Lindner, Julia Schiekel |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Phosphatidylinositol 4
5-Diphosphate Patch-Clamp Techniques Physiology Action Potentials Nerve Tissue Proteins CHO Cells Biology Transfection Cricetulus Potassium Channels Tandem Pore Domain Physiology (medical) Cricetinae Potassium Channel Blockers Animals Microscopy Interference Myocytes Cardiac Patch clamp Enzyme Inhibitors Receptor Protein kinase C Phospholipase C Endothelin-1 Hydrolysis Hydrogen-Ion Concentration Receptor Endothelin A Endothelin 1 Molecular biology Potassium channel Cell biology Rats Enzyme Activation Kinetics Microscopy Fluorescence Type C Phospholipases Signal transduction Cardiology and Cardiovascular Medicine Endothelin receptor Ion Channel Gating Signal Transduction |
| Zdroj: | Cardiovascular research. 97(1) |
| ISSN: | 1755-3245 |
| Popis: | The two-pore-domain potassium channel TASK-1 is robustly inhibited by the activation of receptors coupled to the Gaq 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 (ITASK) in cardiomyocytes. Methods and results Patch-clamp measurements were carried out in isolated rat cardiomyocytes. ITASK was identified by extracellular acid- ification to pH 6.0 and by the application of the TASK-1 blockers A293 and A1899. Endothelin-1 completely inhibited ITASK 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 ITASK 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 ITASK 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 ITASK 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 ITASK. |
| Databáze: | OpenAIRE |
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