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
Block of the background K+ channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor / A. Barbuti, S. Ishii, T. Shimizu, R.B. Robinson, S.J. Feinmark. - In: AMERICAN JOURNAL OF PHYSIOLOGY. HEART AND CIRCULATORY PHYSIOLOGY. - ISSN 0363-6135. - 282:6(2002 Jun), pp. H2024-H2030.
|Titolo:||Block of the background K+ channel TASK-1 contributes to arrhythmogenic effects of platelet-activating factor|
BARBUTI, ANDREA FRANCESCO (Primo)
|Parole Chiave:||two-pore domain potassium channels; Kcnk3 ventricular myocytes; inflammatory lipids; mouse|
|Data di pubblicazione:||giu-2002|
|Appare nelle tipologie:||01 - Articolo su periodico|