Block of recombinant KCNQ1/KCNE1 K+ channels (IKs) by intracellular Na+ and its implications on action potential repolarization.
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 Delta ("electrical" distance of the block site) approximately 0.6 and K(d)(0) (apparent dissociation constant at 0 mV) approximately 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).
Orikabe
Minako
M
Department of Cardiovascular Medicine, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510 Japan.
Hirano
Yuji
Y
Isobe
Mitsuaki
M
Hiraoka
Masayasu
M
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels / Q000235:genetics / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D012964:Sodium / Q000493:pharmacokinetics*
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D012964:Sodium