Larger transient outward K+ current and shorter action potential duration in Gα11 mutant mice

The α1-adrenoceptor as well as the AT1- and the ETA-receptor couple to G-proteins of the Gαq/11 family and contribute to the regulation of the transient outward K+ current (Ito,f) under pathological conditions such as cardiac hypertrophy or failure. This suggests an important role of Gαq/11-signalling in the physiological regulation of Ito,f. Here, we investigate mice deficient of the Gα11 protein (gna11−/−) to clarify the physiological role of Gα11 signalling in cardiac ion channel regulation. Myocytes from endocardial and epicardial layers were isolated from the left ventricular free wall and investigated using the ruptured-patch whole-cell patch-clamp technique. At +40 mV, epicardial myocytes from gna11−/− mice displayed a 23% larger Ito,f than controls (52.6 ± 4.1 pApF−1, n = 20 vs 42.7 ± 2.8 pApF−1, n = 26, p < 0.05). Endocardial Ito,f was similar in gna11−/− mice and controls. With the except of minor changes in endocardial myocytes, Ito,f kinetics were similar in both groups. In the epicardial layer, western blot analysis revealed a 19% higher expression of the K+-channel α-subunit Kv4.2 in gna11−/− mice than in wild type (wt; p < 0.05). The β-subunit KChIP2b was upregulated by 102% in epicardial myocytes of gna11−/− mice (p < 0.01, n = 4). Consistent with the difference in Ito,f, action potential duration was shorter in epicardial cells of gna11−/− mice than in wt (p < 0.05), while no difference was found in endocardial myocytes. These results suggest that Gα11-coupled signalling is a central pathway in the regulation of Ito,f. It physiologically exerts a tonic inhibitory influence on the expression of Ito,f and thereby contributes to the regulation of cardiac repolarisation.