Block of the background K(+) channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor.
Platelet-activating factor (PAF), an inflammatory phospholipid, induces ventricular arrhythmia via an unknown ionic mechanism. We can now link PAF-mediated cardiac electrophysiological effects to inhibition of a two-pore domain K(+) channel [TWIK-related acid-sensitive K(+) background channel (TASK-1)]. Superfusion of carbamyl-PAF (C-PAF), a stable analog of PAF, over murine ventricular myocytes causes abnormal automaticity, plateau phase arrest of the action potential, and early afterdepolarizations in paced and quiescent cells from wild-type but not PAF receptor knockout mice. C-PAF-dependent currents are insensitive to Cs(+) and are outwardly rectifying with biophysical properties consistent with a K(+)-selective channel. The current is blocked by TASK-1 inhibitors, including protons, Ba(2+), Zn(2+), and methanandamide, a stable analog of the endogenous lipid ligand of cannabinoid receptors. In addition, when TASK-1 is expressed in CHO cells that express an endogenous PAF receptor, superfusion of C-PAF decreases the expressed current. Like C-PAF, methanandamide evoked spontaneous activity in quiescent myocytes. C-PAF- and methanandamide-sensitive currents are blocked by a specific protein kinase C (PKC) inhibitor, implying overlapping signaling pathways. In conclusion, C-PAF blocks TASK-1 or a closely related channel, the effect is PKC dependent, and the inhibition alters the electrical activity of myocytes in ways that would be arrhythmogenic in the intact heart.
Barbuti
Andrea
A
Center for Molecular Therapeutics, Department of Pharmacology, Columbia University, New York, New York 10032, USA.
Ishii
Satoshi
S
Shimizu
Takao
T
Robinson
Richard B
RB
Feinmark
Steven J
SJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D001464:Barium / Q000494:pharmacology; D004553:Electric Conductivity; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology; D006352:Heart Ventricles / Q000648:ultrastructure; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000502:physiology; D024683:Potassium Channels, Tandem Pore Domain; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011522:Protons; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D015032:Zinc / Q000494:pharmacology
D001095:Arachidonic Acids; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D011522:Protons; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C053479:1-O-hexadecyl-2-N-methylcarbamylphosphatidylcholine; C088155:methanandamide; C420132:potassium channel subfamily K member 3; D001464:Barium; D011493:Protein Kinase C; D015032:Zinc