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The inhibition of the potassium channel TASK-1 in rat cardiac muscle by endothelin-1 is mediated by phospholipase C.
- Source :
-
Cardiovascular research [Cardiovasc Res] 2013 Jan 01; Vol. 97 (1), pp. 97-105. Date of Electronic Publication: 2012 Sep 12. - Publication Year :
- 2013
-
Abstract
- 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.<br />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.<br />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).
- Subjects :
- Action Potentials
Animals
CHO Cells
Cricetinae
Cricetulus
Enzyme Activation
Enzyme Inhibitors pharmacology
Hydrogen-Ion Concentration
Hydrolysis
Kinetics
Microscopy, Fluorescence
Microscopy, Interference
Myocytes, Cardiac drug effects
Nerve Tissue Proteins
Patch-Clamp Techniques
Phosphatidylinositol 4,5-Diphosphate metabolism
Potassium Channels, Tandem Pore Domain genetics
Potassium Channels, Tandem Pore Domain metabolism
Rats
Receptor, Endothelin A genetics
Receptor, Endothelin A metabolism
Signal Transduction drug effects
Transfection
Type C Phospholipases antagonists & inhibitors
Endothelin-1 pharmacology
Ion Channel Gating
Myocytes, Cardiac enzymology
Potassium Channel Blockers pharmacology
Potassium Channels, Tandem Pore Domain antagonists & inhibitors
Type C Phospholipases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1755-3245
- Volume :
- 97
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cardiovascular research
- Publication Type :
- Academic Journal
- Accession number :
- 22977011
- Full Text :
- https://doi.org/10.1093/cvr/cvs285