title: Modulation of the transient outward current (Ito) in rat cardiac myocytes and human Kv4.3 channels by mefloquine.
abstract: The antimalarial drug mefloquine, is known to be a potassium channel blocker, although its mechanism of action has not being elucidated and its effects on the transient outward current (Ito) and the molecular correlate, the Kv4.3 channel has not being studied. Here, we describe the mefloquine-induced inhibition of the rat ventricular Ito and of CHO cells co-transfected with human Kv4.3 and its accessory subunit hKChIP2C by whole-cell voltage-clamp. Mefloquine inhibited rat Ito and hKv4.3+KChIP2C currents in a concentration-dependent manner with a limited voltage dependence and similar potencies (IC50=8.9μM and 10.5μM for cardiac myocytes and Kv4.3 channels, respectively). In addition, mefloquine did not affect the activation of either current but significantly modified the hKv4.3 steady-state inactivation and recovery from inactivation. The effects of this drug was compared with that of 4-aminopyridine (4-AP), a well-known potassium channel blocker and its binding site does not seem to overlap with that of 4-AP.
authors.affiliation: Laboratory of Cardiac Biophysics, Instituto de Fisiología and Facultad de Medicina, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: E J
authors.initials: EJ
authors.lastname: Perez-Cortes
authors.affiliation: Laboratory of Cardiac Biophysics, Instituto de Fisiología and Facultad de Medicina, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: A A
authors.initials: AA
authors.lastname: Islas
authors.affiliation: Laboratory of Cardiac Biophysics, Instituto de Fisiología and Facultad de Medicina, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: J P
authors.initials: JP
authors.lastname: Arevalo
authors.affiliation: Laboratory of Cardiac Biophysics, Instituto de Fisiología and Facultad de Medicina, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: C
authors.initials: C
authors.lastname: Mancilla
authors.affiliation: Laboratory of Cardiac Biophysics, Instituto de Fisiología and Facultad de Medicina, Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: E
authors.initials: E
authors.lastname: Monjaraz
authors.affiliation: Laboratory of Cardiac Biophysics, Instituto de Fisiología and Facultad de Medicina, Universidad Autónoma de Puebla, Puebla, Mexico. Electronic address: eduardo.salinas@correo.buap.mx.
authors.forename: E M
authors.initials: EM
authors.lastname: Salinas-Stefanon
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D000962:Antimalarials / Q000378:metabolism / Q000633:toxicity*; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects*; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D015767:Mefloquine / Q000378:metabolism / Q000633:toxicity*; D062105:Molecular Docking Simulation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000378:metabolism / Q000633:toxicity*; D011485:Protein Binding; D017208:Rats, Wistar; D051672:Shal Potassium Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: D000962:Antimalarials; C497021:KCND3 protein, human; C496752:KCNIP2 protein, human; D051605:Kv Channel-Interacting Proteins; D026902:Potassium Channel Blockers; D051672:Shal Potassium Channels; D015761:4-Aminopyridine; D011188:Potassium; D015767:Mefloquine
keywords: 4-AP; Docking; K(v)4.3; K+ channel; Mefloquine; Myocyte