In an accompanying abstract we show that RGS4 deficient mice are predisposed to atrial fibrillation. We thus investigated potential electrophysiological substrates that might underlie this observation.Methods
In vitro electrophysiological studies were performed using single atrial cardiomyocytes isolated from RGS4 -/- and RGS4 + / + littermates by enzymatic digestion. Cells were studied using the patch-clamp technique. Data are compared using Student t-test (* p < 0.05, ** p < 0.001).Results
Paradoxically, atrial cells isolated from RGS4 -/- animals show more rapid activation and deactivation kinetics of G-protein gated inward rectifying potassium (GIRK) current (lag + TTP 0.79 ± 0.06** ms, tau ac 218 ± 22* ms, tau inac 2056 ± 250* ms) than cells from RGS4 + / + animals (lag + TTP 1.35 ± 0.12 ms, tau ac 370 ± 45 ms, tau inac 3512 ± 580 ms). Furthermore, the action potential parameters, measured as total depolarisation, APD50, APD90 and total duration, were not significantly different between the two groups. Finally, we examined rate dependence of action potential duration by constructing single-cell restitution curves. The slope of the restitution curves in its linear phase (30 to 70 ms) was steeper in the RGS4 -/- mice (slope 1.07 ± 0.09) compared to RGS4 + / + mice (slope 0.59 ± 0.05): this is a potential proarrhytmic substrate.Conclusions
This study shows that deletion of RGS4 in mice leads to paradoxical changes in GIRK channel kinetics and no changes in action potential duration. However, the mice do have potentially proarrhythmic changes in restitution properties and this might underlie a predisposition to atrial fibrillation.