Electrophysiologic perturbations and arrhythmogenic activity caused by activation of the Fas receptor in murine ventricular myocytes: role of the inositol trisphosphate pathway.
BACKGROUND
Experimental evidence suggests a major role for Fas receptor activation in a wide range of myocardial pathologies. Because clinical situations, which are likely to be associated with Fas activation, are accompanied by a variety of ventricular arrhythmias, the major goal of this study was to investigate the ionic mechanisms responsible for these phenomena.


RESULTS
To delineate the origin of Fas-mediated electrophysiologic perturbations, the transient outward K+ current I(to) and the L-type Ca2+ current I(Ca,L) were studied in murine ventricular myocytes treated with the Fas-activating monoclonal antibody Jo2. Jo2 decreased I(to) (4.36 +/- 1.2 pA/pF vs 17.48 +/- 2.36 pA/pF in control, V(M) = +50 mV; P < 0.001) and increased I(Ca,L) (-13.17 +/- 1.38 pA/pF vs -3.94 +/- 0.78 pA/pF in control, V(M) = 0 mV; P < 0.001). Pretreatment of ventricular myocytes with ryanodine or thapsigargin prevented the electrophysiologic effects of Jo2, suggesting that [Ca2+]i elevation is important for Fas-mediated action. In agreement with our previous studies demonstrating dependence of Fas-based myocyte dysfunction on an intact inositol trisphosphate (1,4,5-IP3) pathway, the effects of Jo2 on I(to) and I(Ca,L) were prevented by the phospholipase C (generates 1,4,5-IP3) blocker U73122, and by xestospongin C (tested with I(to)), a specific blocker of IP3-operated sarcoplasmic reticulum Ca2+ release channels. Furthermore, intracellular perfusion with 1,4,5-IP3, but not with 1,3,4-IP3, caused electrophysiologic effects resembling those of Jo2.


CONCLUSIONS
Decreased I(to) and increased I(Ca,L) underlie Fas-induced action potential alterations and arrhythmias in murine ventricular myocytes, effects that appear to be mediated by 1,4,5-IP3-induced intracellular calcium release.
Bruce Rappaport Faculty of Medicine, The Bernard Katz Minerva Center for Cell Biophysics, Technion-Israel Institute of Technology, Haifa.
M
M
Shilkrut
O
O
Gealekman
D
D
Rosen
G
G
Berke
E
E
Woodcock
O
O
Binah
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D020746:Calcium Channels, L-Type / Q000502:physiology; D004594:Electrophysiology; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D007293:Inosine Triphosphate / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D015221:Potassium Channels / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016276:Ventricular Function; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D000911:Antibodies, Monoclonal; D020746:Calcium Channels, L-Type; D015221:Potassium Channels; D012333:RNA, Messenger; D019014:fas Receptor; D007293:Inosine Triphosphate