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

Author:

Barbuti Andrea1,Ishii Satoshi2,Shimizu Takao2,Robinson Richard B.1,Feinmark Steven J.1

Affiliation:

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

Abstract

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.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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