| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Articles in PresS, published online ahead of print January 31, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00956.2001
Submitted on November 2, 2001
Accepted on January 30, 2002
1 Pharmacology, Columbia University, New York, NY, USA
2 Biochemistry and Molecular Biology, University of Tokyo, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: sjf1{at}columbia.edu.
Platelet-activating factor (PAF), an inflammatory phospholipid, induces ventricular arrhythmia via an unknown ionic mechanism. We now link PAF-mediated cardiac electrophysiologic effects to inhibition of the two-pore domain K+ channel, TASK-1. Superfusion of carbamyl-platelet-activating factor (C-PAF), a stable analogue 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 analogue of the endogenous lipid ligand of cannabanoid receptors. In addition, when TASK-1 is expressed in CHO cells that express an endogenous PAFR, 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 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.
This article has been cited by other articles:
|
|
 |
|
  F. Charpentier Understanding the cardiac role of K2P channels: A new TASK for electrophysiologists Cardiovasc Res, July 1, 2007; 75(1): 5 - 6. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Mathie Neuronal two-pore-domain potassium channels and their regulation by G protein-coupled receptors J. Physiol., January 15, 2007; 578(2): 377 - 385. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E Clarke, E. L Veale, P. J Green, H. J Meadows, and A. Mathie Selective block of the human 2-P domain potassium channel, TASK-3, and the native leak potassium current, IKSO, by zinc J. Physiol., October 1, 2004; 560(1): 51 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Lauritzen, M. Zanzouri, E. Honore, F. Duprat, M. U. Ehrengruber, M. Lazdunski, and A. J. Patel K+-dependent Cerebellar Granule Neuron Apoptosis: ROLE OF TASK LEAK K+ CHANNELS J. Biol. Chem., August 22, 2003; 278(34): 32068 - 32076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Bayliss, J. E. Sirois, and E. M. Talley The TASK Family: Two-Pore Domain Background K+ Channels Mol. Interv., June 1, 2003; 3(4): 205 - 219. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
