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Am J Physiol Heart Circ Physiol 282: H2024-H2030, 2002. First published January 31, 2002; doi:10.1152/ajpheart.00956.2001
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Vol. 282, Issue 6, H2024-H2030, June 2002

Block of the background K+ channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor

Andrea Barbuti1, Satoshi Ishii2, Takao Shimizu2, Richard B. Robinson1, and Steven J. Feinmark1

1 Center for Molecular Therapeutics, Department of Pharmacology, Columbia University, New York, New York 10032; and 2 Department of Biochemistry and Molecular Biology, University of Tokyo, Tokyo, 113-003 Japan

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, Ba2+, Zn2+, and methanandamide, a stable analog of the endogenous lipid ligand of cannabanoid 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.

two-pore domain potassium channels; Kcnk3 ventricular myocytes; inflammatory lipids; mouse


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