Activation of protein kinase C epsilon inhibits the two-pore domain K+ channel, TASK-1, inducing repolarization abnormalities in cardiac ventricular myocytes.
Activation of the platelet-activating factor (PAF) receptor leads to a decrease in outward current in murine ventricular myocytes by inhibiting the TASK-1 channel. TASK-1 carries a background or "leak" current and is a member of the two-pore domain potassium channel family. Its inhibition is sufficient to delay repolarization, causing prolongation of the action potential duration, and in some cases, early after depolarizations. We set out to determine the cellular mechanisms that control regulation of TASK-1 by PAF. Inhibition of TASK-1 via activation of the PAF receptor is protein kinase C (PKC)-dependent. Using isoform-specific PKC inhibitor or activator peptides in patch clamp experiments, we now demonstrate that activation of PKCepsilon is both necessary and sufficient to regulate murine TASK-1 current in a heterologous expression system and to induce repolarization abnormalities in isolated myocytes. Furthermore, site-directed mutagenesis studies have identified threonine 381, in the C-terminal tail of murine TASK-1, as a critical residue in this regulation.
Besana
Alessandra
A
Center for Molecular Therapeutics, Department of Pharmacology, Columbia University, New York, New York 10032, USA.
Barbuti
Andrea
A
Tateyama
Miyuki A
MA
Symes
Aviva J
AJ
Robinson
Richard B
RB
Feinmark
Steven J
SJ
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004553:Electric Conductivity; D004789:Enzyme Activation; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010972:Platelet Activating Factor / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024683:Potassium Channels, Tandem Pore Domain; D011493:Protein Kinase C / Q000378:metabolism*; D051744:Protein Kinase C-epsilon; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D013329:Structure-Activity Relationship; D014162:Transfection
D009419:Nerve Tissue Proteins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C420132:potassium channel subfamily K member 3; C497256:Prkce protein, mouse; D011493:Protein Kinase C; D051744:Protein Kinase C-epsilon