RT Journal Article
T1 Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents
A1 Gómez García, Ricardo
A1 Caballero Collado, Ricardo
A1 Barana Muñoz, Adriana
A1 Amorós García, Irene
A1 de Palm, Sue Haida
A1 Matamoros, Marcos
A1 Núñez, Mercedes
A1 Pérez Hernández, Marta
A1 Iriepa, Isabel
A1 Tamargo Menéndez, Juan
A1 Delpón Mosquera, María Eva
AB Aims: We hypothesize that some drugs, besides flecainide, increase the inward rectifier current (IK1) generated by Kir2.1 homotetramers (IKir2.1) and thus, exhibit pro- and/or antiarrhythmic effects particularly at the ventricular level. To test this hypothesis, we analysed the effects of propafenone, atenolol, dronedarone, and timolol on Kir2.x channels.Methods and results: Currents were recorded with the patch-clamp technique using whole-cell, inside-out, and cell-attached configurations. Propafenone (0.1 nM-1 µM) did not modify either IK1 recorded in human right atrial myocytes or the current generated by homo- or heterotetramers of Kir2.2 and 2.3 channels recorded in transiently transfected Chinese hamster ovary cells. On the other hand, propafenone increased IKir2.1 (EC50 = 12.0 ± 3.0 nM) as a consequence of its interaction with Cys311, an effect which decreased inward rectification of the current. Propafenone significantly increased mean open time and opening frequency at all the voltages tested, resulting in a significant increase of the mean open probability of the channel. Timolol, which interacted with Cys311, was also able to increase IKir2.1. On the contrary, neither atenolol nor dronedarone modified IKir2.1. Molecular modelling of the Kir2.1-drugs interaction allowed identification of the pharmacophore of drugs that increase IKir2.1.Conclusions: Kir2.1 channels exhibit a binding site determined by Cys311 that is responsible for drug-induced IKir2.1 increase. Drug binding decreases channel affinity for polyamines and current rectification, and can be a mechanism of drug-induced pro- and antiarrhythmic effects not considered until now.
PB European Society of Cardiology
SN 0008-6363
YR 2014
FD 2014-11-01
LK https://hdl.handle.net/20.500.14352/92156
UL https://hdl.handle.net/20.500.14352/92156
LA eng
NO Gómez R, Caballero R, Barana A, Amorós I, De Palm SH, Matamoros M, Núñez M, Pérez-Hernández M, Iriepa I, Tamargo J, Delpón E. Structural basis of drugs that increase cardiac inward rectifier Kir2.1 currents. Cardiovasc Res. 2014 Nov 1;104(2):337-46. doi: 10.1093/cvr/cvu203
NO Ministerio de Ciencia e Innovación
NO Instituto de Salud Carlos III
NO Centro Nacional de Investigaciones Cardiovasculares
NO Comunidad de Madrid
NO Sociedad Española de Cardiología
DS Docta Complutense
RD 12 abr 2025