KvBeta2 Alters Kv1 Surface Expression and Modulates Electrophysiologic Properties in Ventricular Cardiomyocytes

Introduction The voltage‐gated potassium (Kv) channels regulate the resting membrane potential and the repolarization phase of the cardiac action potential. Members of the Kv1 and Kv4 family associate with ancillary subunits, such as Kvβ 1–3, that modify channel kinetics, gating and trafficking. Although Kvβ1 has been shown to regulate I to and I Kslow currents in the heart, the role of Kvβ2 in regulating myocardial potassium conductances is unknown. In heterologous expression systems, Kvβ2 increases surface expression of Kv1 channels, shifts the activation potential of Kv1 currents to more polarized voltages, and increases the inactivation of inactivating Kv1 currents, but its role in regulating native cardiac channels remains unknown. Hence, to identify the role of Kvβ2 in the heart, we examined the distribution and activity of Kv1 and Kv4 channels in cardiac myocytes from wild‐type (WT) and Kvβ2‐null mice (KO). Methods Western blotting and confocal microscopy were used to determine the abundance and localization of Kvβ2, Kv1.4 and Kv1.5 proteins in heart and isolated cardiomyocytes. Action potentials and whole‐cell Kv currents were recorded from freshly isolated mouse cardiac myocytes using standard patch clamp methodologies. Results Immunoprecipitation of Kvβ2 from the heart resulted in co‐immunoprecipitation of Kv1.5 and Kv1.4. In comparison with WT cardiac myocytes, the surface expression of Kv1.5 was reduced in KO myocytes. Ventricular myocytes from KO mice had significantly lower peak Kv current density (p<0.01) and component Kv current densities as determined by triexponential curve fitting suggesting reduced I Kur and I to (p<0.01, n=34 cells, N=10 mice), consistent with a decrease in Kv1.4 and Kv1.5 channel density and a shift in the voltage‐dependence of the activation of the current. The duration of action potentials (APD 20, APD90) recorded from myocytes isolated from the right ventricle was significantly prolonged in KO mice (p<0.01, n=32 cells, N=11 mice) when compared with WT cardiac myocytes. Simulation of action potentials in CellML using experimental voltage clamp data resulted in similarly prolonged APs, as did partial pharmacological blockade of Kv1 channels with 4‐aminopyridine. Conclusion Mouse cardiac myocytes express Kvβ2, which interacts primarily with Kv1.4 and Kv1.5 channels. Association with Kvβ2 regulates Kv1 expression and function in the sarcolemma, and thereby, the repolarization phase of the action potential.