Abstract 14194: Genetic Ablation of Potassium Channel Subunit Kvβ2 Slows Repolarization in the Cardiac Septum and Leads to Cardiac Remodeling
Multiple voltage-gated (Kv) channels are expressed in the heart and they regulate the resting membrane potential and the repolarization phase of the action potential. Members of the Kv1 and Kv4 family associate with ancillary β-subunits (Kvβ1-3) that modify channel kinetics and gating. Previous studies have shown that Kvβ regulates the IKslow kinetics in cardiac myocytes, but, the specific role of Kvβ2 remains unknown. In heterologous expression systems, Kvβ2 increases the inactivation of Kv1 and Kv4 proteins and shifts the activation potential of Kv1.5 to depolarized potentials. The role of Kvβ2 in regulating cardiac K conductances has not been studied. Accordingly, we examined cardiac function and excitability in Kvβ2-null mice. Physical and hemodynamic measures were collected on adult male mice (20±1 wk) to assess non-cardiac effects. Kvβ2-null mice demonstrated normal reproductive capability and lifespan, but in comparison with wild-type (WT; n=12) mice, the Kvβ2-null mice (n=13) had reduced body weight (22.7±0.73 vs. 25.9±1.3g, p=0.03) and reduced LV mass:tibia ratio (0.0029±0.00014 vs. 0.004±0.00024g/mm, p=0.0007). Echocardiographic recordings support the finding of left ventricular atrophy, with the Kvβ2-null mice having reduced left ventricular long-axis dimension (6.05±0.11 vs. 6.43±0.10mm, p<0.02) and smaller end diastolic volume (34.7±1.76 vs. 40.0±1.45µL, p<0.03). The duration of the action potential (APD90) recorded from myocytes isolated from the left ventricular epicardium showed frequency-dependent shortening in WT (p<0.05) but not Kvβ2-null mice. Whole-cell patch-clamp currents of epicardial myocytes showed no difference in the inactivation kinetics of Kv currents between WT and Kvβ2-null. However, Kv currents in myocytes isolated from the interventricular septum displayed a decreased rate in the rapid phase of inactivation in Kvβ2-null (n=6) compared with WT (n=6) (τfast =65.7±2.6 vs. 53.5±1.6ms, p<0.01). Deletion of Kvβ2 did not alter Kv current densities in the epicardium or in the septum. These data suggest that Kvβ2 regulates cardiac development and that it plays a distinct, region-specific role in regulating frequency-dependent changes in the action potential and the spread of excitation in the heart.
- © 2011 by American Heart Association, Inc.