Block of Recombinant KCNQ1/KCNE1 K⁺ Channels (I_Ks) by Intracellular Na⁺ and Its Implications on Action Potential Repolarization

Abstract

I_Ks, the slow component of delayed rectifier K⁺ current, plays an important role for the repolarization of ventricular action potential. We investigated the block of I_Ks by intracellular Na⁺ ([Na⁺]_i), using a heterologous expression system (KCNQ1/KCNE1 expressed in COS7 cells), since this well-known blocking action on various K⁺ channels has not been fully or quantitatively characterized in I_Ks current. The Na⁺ block of I_Ks was concentration- and voltage-dependent and was described by a conventional binding-site model (Woodhull AM: J Gen Physiol 61: 687–708, 1973). In physiological ionic conditions, the blocking action was operating noticeably with Δ ("electrical" distance of the block site) ∼0.6 and K_d(0) (apparent dissociation constant at 0 mV) ∼300 mM. Because K_d(0) was a function of intra- and extracellular K⁺ concentrations, changes in ionic environments not only of [Na⁺]_i, but also of [K⁺]_o, affected the amplitude of I_Ks through the modulation of the Na⁺ block. Based on these experimental data, we analyzed the effects of Na⁺ block on action potentials by a computer simulation study, using the Luo-Rudy model. In a physiological ionic environment, the Na⁺ block of I_Ks contributed little to modifying action potentials. However, when action potential duration (APD) was marginally prolonged because of decreased I_Ks, as observed in M cells under the conditions of bradycardia and low [K⁺]_o, the Na⁺ block of I_Ks may contribute to arrhythmogenesis through the facilitation of early afterdepolarizations (EADs).