Dihydropyridine Ca2+ channel antagonists and agonists block Kv4.2, Kv4.3 and Kv1.4 K+ channels expressed in HEK293 cells.
(1) We have determined the molecular basis of nicardipine-induced block of cardiac transient outward K(+) currents (I(to)). Inhibition of I(to) was studied using cloned voltage-dependent K(+) channels (Kv) channels, rat Kv4.3L, Kv4.2, and Kv1.4, expressed in human embryonic kidney cell line 293 (HEK293) cells. (2) Application of the dihydropyridine Ca(2+) channel antagonist, nicardipine, accelerated the inactivation rate and reduced the peak amplitude of Kv4.3L currents in a concentration-dependent manner (IC(50): 0.42 micro M). The dihydropyridine (DHP) Ca(2+) channel agonist, Bay K 8644, also blocked this K(+) current (IC(50): 1.74 micro M). (3) Nicardipine (1 micro M) 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; IC(50)'s were 0.80 and 0.62 micro M, respectively. (6) Thus, at submicromolar concentrations, DHP Ca(2+) antagonist and agonist inhibit Kv4.3L and have similar inhibiting effects on other components of cardiac I(to), Kv4.2 and Kv1.4.
Hatano
Noriyuki
N
Department of Molecular and Cellular Pharmacology, Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan.
Ohya
Susumu
S
Muraki
Katsuhiko
K
Giles
Wayne
W
Imaizumi
Yuji
Y
D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002460:Cell Line; D004095:Dihydropyridines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051665:Kv1.4 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D015221:Potassium Channels / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; C496977:KCNA4 protein, human; C497018:KCND2 protein, human; C497021:KCND3 protein, human; D051665:Kv1.4 Potassium Channel; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels