title: The inhibition of the potassium channel TASK-1 in rat cardiac muscle by endothelin-1 is mediated by phospholipase C.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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).
authors.affiliation: Institute of Physiology and Pathophysiology,  University of Marburg, Deutschhausstrasse 2, Marburg 35037,  Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schiekel
authors.forename: Moritz
authors.initials: M
authors.lastname: Lindner
authors.forename: Andrea
authors.initials: A
authors.lastname: Hetzel
authors.forename: Konstantin
authors.initials: K
authors.lastname: Wemhöner
authors.forename: Vijay
authors.initials: V
authors.lastname: Renigunta
authors.forename: Günter
authors.initials: G
authors.lastname: Schlichthörl
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.forename: Dominik
authors.initials: D
authors.lastname: Oliver
authors.forename: Jürgen
authors.initials: J
authors.lastname: Daut
mesh_terms: D000200:Action Potentials; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019332:Endothelin-1 / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D015640:Ion Channel Gating; D007700:Kinetics; D008856:Microscopy, Fluorescence; D008857:Microscopy, Interference; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D009419:Nerve Tissue Proteins; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D044022:Receptor, Endothelin A; C420132:potassium channel subfamily K member 3; D010738:Type C Phospholipases