Dihydropyridine Ca2+ channel antagonists and agonists block Kv4.2, Kv4.3 and Kv1.4 K+ channels expressed in HEK293 cells

Abstract

1. We have determined the molecular basis of nicardipine-induced block of cardiac transient outward K+ currents (Ito). Inhibition of Ito was studied using cloned voltage-dependent K+ channels (Kv) channels, rat Kv4.3L, Kv4.2, and Kv1.4, expressed in human embryonic kindey cell line 293 (HEK293) cells. 2. Application of the dihydropyridine Ca2+ channel antagonist, nicardipine, accelerated the inactivation rate and reduced the peak amplitude of Kv4.3L currents in a concentration-dependent manner (IC50: 0.42 μM). The dihydropyridine (DHP) Ca2+ channel agonist, Bay K 8644, also blocked this K+ current (IC50: 1.74 μM). 3. Nicardipine (1 μM) slightly, but significantly, shifted the voltage dependence of activation and steady-state inactivation to more negative potentials, and also slowed markedly the recovery from inactivation of Kv4.3L currents. 4. Coexpression of K+ channel-interacting protein 2 (KChIP2) significantly slowed the inactivation of Kv4.3L currents as expected. However, the features of DHP-induced block of K+ current were not substantially altered. 5. Nicardipine exhibited similar block of Kv1.4 and Kv4.2 channels stably expressed in HEK293 cells; IC50's were 0.80 and 0.62 μM, respectively. 6. Thus, at submicromolar concentrations, DHP Ca2+ antagonist and agonist inhibit Kv4.3L and have similar inhibiting effects on other components of cardiac Ito, Kv4.2 and Kv1.4.