RT Journal Article
T1 Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification
A1 Caballero Collado, Ricardo
A1 Dolz Gaitón, Pablo
A1 Gómez García, Ricardo
A1 Amorós García, Irene
A1 Barana Muñoz, Adriana
A1 González de la Fuente, Marta
A1 Osuna, Lourdes
A1 Duarte, Juan
A1 López Izquierdo, Angélica
A1 Moraleda, Ignacio
A1 Gálvez Ruano, Enrique
A1 Sánchez Chapula, José Antonio
A1 Tamargo Menéndez, Juan
A1 Delpón Mosquera, María Eva
AB Both increase and decrease of cardiac inward rectifier current (I(K1)) are associated with severe cardiac arrhythmias. Flecainide, a widely used antiarrhythmic drug, exhibits ventricular proarrhythmic effects while effectively controlling ventricular arrhythmias associated with mutations in the gene encoding Kir2.1 channels that decrease I(K1) (Andersen syndrome). Here we characterize the electrophysiological and molecular basis of the flecainide-induced increase of the current generated by Kir2.1 channels (I(Kir2.1)) and I(K1) recorded in ventricular myocytes. Flecainide increases outward I(Kir2.1) generated by homotetrameric Kir2.1 channels by decreasing their affinity for intracellular polyamines, which reduces the inward rectification of the current. Flecainide interacts with the HI loop of the cytoplasmic domain of the channel, Cys311 being critical for the effect. This explains why flecainide does not increase I(Kir2.2) and I(Kir2.3), because Kir2.2 and Kir2.3 channels do not exhibit a Cys residue at the equivalent position. We further show that incubation with flecainide increases expression of functional Kir2.1 channels in the membrane, an effect also determined by Cys311. Indeed, flecainide pharmacologically rescues R67W, but not R218W, channel mutations found in Andersen syndrome patients. Moreover, our findings provide noteworthy clues about the structural determinants of the C terminus cytoplasmic domain of Kir2.1 channels involved in the control of gating and rectification.
PB National Academy of Sciences
SN 0027-8424
YR 2010
FD 2010-08-31
LK https://hdl.handle.net/20.500.14352/92209
UL https://hdl.handle.net/20.500.14352/92209
LA eng
NO Caballero R, Dolz-Gaitón P, Gómez R, Amorós I, Barana A, González de la Fuente M, Osuna L, Duarte J, López-Izquierdo A, Moraleda I, Gálvez E, Sánchez-Chapula JA, Tamargo J, Delpón E. Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification. Proc Natl Acad Sci U S A. 2010 Aug 31;107(35):15631-6. doi: 10.1073/pnas.1004021107
NO Ministerio de Educación yCiencia
NO Ministerio de Sanidad y Consumo
NO Instituto deSalud Carlos III
NO UniversidadComplutense de Madrid
NO Fundación LILL
NO Centro Nacional de Investigaciones Cardiovasculares
DS Docta Complutense
RD 9 abr 2025