Background: TRPC3 was recently suggested as a player in the pathogenesis of cardiac hypertrophy. Nonetheless, the potential proarrhythmogenic role of TRPC3 is incompletely understood. Using a TRPC3 transgenic overexpression mouse model, we examined the involvement of TRPC3 in cardiac actions of Angiotensin II (AngII), a pathophysiologically relevant mediator and activator of GPCR/Gq/TRPC3 signaling.Methods: Single ventricular myocytes were isolated and field-stimulated at 1 Hz at 37C to determine AngII effects on sarcomere shortening and Ca2+ transients by an edge detection and epifluorescence system, respectively.Results: Ca2+ transients were significantly higher (p<0.05; N=60) in myocytes from TRPC3-overexpressing mice ([Ca2+] F/F0 0.3540.024) as compared to WT ([Ca2+] F/F0 0.2620.021). Sarcomere shortening showed no significant difference between the two groups (3.80.69% vs. 3.520.65%;N=10) whereas sarcoplasmic reticulum- loading, estimated via rapid application of caffeine (20mM), was significantly increased up to 40% in TRPC3-overexpressing myocytes as compared to WT (p<0.05; N=43).Importantly, AngII (100nM) induced a rise in diastolic Ca2+ levels, which was accompanied by irregular contractions in TRPC3 overexpressing but not in WT myocytes. Diastolic [Ca2+] F/F0 rise was 0.240.019 in TRPC3-overexpressing accompanied by 39 arrhythmic events, while WT only showed a slight rise of the diastolic Ca2+ level and no arrhythmic events. Pyr3 (10 ?M; N=16) suppressed significantly the Ang II-induced rise and all arrhythmic events. Similarly, SEA 0400 (1 ?M; N=14) or KN-93 (1 ?M;N=12) inhibited the rise in the diastolic Ca2+ level significantly and reduced also arrhythmic events significantly.Conclusion: We demonstrate that AngII modulation of cardiac functions is strictly dependent on TRPC3 expression and propose a key role of TRPC channels in AngII- mediated arrhythmogenicity.