| Autor: |
de Benito-Bueno A; Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), 28029 Madrid, Spain., Socuellamos PG; Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), 28029 Madrid, Spain., Merinero YG; Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), 28029 Madrid, Spain., Cercos P; Instituto de Química Médica (IQM-CSIC), 28029 Madrid, Spain., Izquierdo C; Instituto de Química Médica (IQM-CSIC), 28029 Madrid, Spain., Daniel-Mozo M; Instituto de Química Física Rocasolano, Consejo Superior de Investigaciones Científicas (IQFR-CSIC), 28006 Madrid, Spain., Marín-Olivero I; Nanoscopy-UGR Laboratory, Departamento de Fisicoquímica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Campus Cartuja, Universidad de Granada, 18071 Granada, Spain., Perez-Lara A; Nanoscopy-UGR Laboratory, Departamento de Fisicoquímica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Campus Cartuja, Universidad de Granada, 18071 Granada, Spain.; Department of Neurobiology, Max Planck Institute for Multidisciplinary Sciences, 37077 Göttingen, Germany., Gonzalez-Vera JA; Nanoscopy-UGR Laboratory, Departamento de Fisicoquímica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Campus Cartuja, Universidad de Granada, 18071 Granada, Spain., Orte A; Nanoscopy-UGR Laboratory, Departamento de Fisicoquímica, Unidad de Excelencia de Química Aplicada a Biomedicina y Medioambiente, Facultad de Farmacia, Campus Cartuja, Universidad de Granada, 18071 Granada, Spain., Albert A; Instituto de Química Física Rocasolano, Consejo Superior de Investigaciones Científicas (IQFR-CSIC), 28006 Madrid, Spain., Martin-Martinez M; Instituto de Química Médica (IQM-CSIC), 28029 Madrid, Spain., Gutierrez-Rodriguez M; Instituto de Química Médica (IQM-CSIC), 28029 Madrid, Spain., Valenzuela C; Instituto de Investigaciones Biomédicas 'Alberto Sols' (CSIC-UAM), 28029 Madrid, Spain.; Spanish Network for Biomedical Research in Cardiovascular Research (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain. |
| Abstrakt: |
The transient outward potassium current ( I tof ) is generated by the activation of K V 4 channels assembled with KChIP2 and other accessory subunits (DPP6 and KCNE2). To test the hypothesis that these subunits modify the channel pharmacology, we analyzed the electrophysiological effects of (3-(2-(3-phenoxyphenyl)acetamido)-2-naphthoic acid) (IQM-266), a new KChIP2 ligand, on the currents generated by K V 4.3/KChIP2, K V 4.3/KChIP2/DPP6 and K V 4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (K V 4.3/KChIP2, K V 4.3/KChIP2/DPP6 or K V 4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of K V 4.3/KChIP2, K V 4.3/KChIP2/DPP6 and K V 4.3/KChIP2/KCNE2 currents, slowing their time course of inactivation in a concentration-, voltage-, time- and use-dependent manner. IQM-266 produced an increase in the charge in K V 4.3/KChIP2 channels that was intensified when DPP6 was present and abolished in the presence of KCNE2. IQM-266 induced an activation unblocking effect during the application of trains of pulses to cells expressing K V 4.3/KChIP2 and K V 4.3/KChIP2/KCNE2, but not in K V 4.3/KChIP2/DPP6 channels. Overall, all these results are consistent with a preferential IQM-266 binding to an active closed state of Kv4.3/KChIP2 and Kv4.3/KChIP2/KCNE2 channels, whereas in the presence of DPP6, IQM-266 binds preferentially to an inactivated state. In conclusion, DPP6 and KCNE2 modify the pharmacological response of K V 4.3/KChIP2 channels to IQM-266. |
