1. Modulation of KV4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2
- Author
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Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Benito-Bueno, Ángela de, Socuéllamos, Paula G., Merinero, Yaiza G., Cercós, Pilar, Izquierdo García, Carolina, Daniel-Mozo, Miguel, Marín-Olivero, Irene, Pérez-Lara, Ángel, González-Vera, Juan A., Orte, Angel, Albert, Armando, Martín-Martínez, Mercedes, Gutiérrez-Rodríguez, Marta, Valenzuela, Carmen, Ministerio de Ciencia e Innovación (España), European Commission, Instituto de Salud Carlos III, Consejo Superior de Investigaciones Científicas (España), Benito-Bueno, Ángela de, Socuéllamos, Paula G., Merinero, Yaiza G., Cercós, Pilar, Izquierdo García, Carolina, Daniel-Mozo, Miguel, Marín-Olivero, Irene, Pérez-Lara, Ángel, González-Vera, Juan A., Orte, Angel, Albert, Armando, Martín-Martínez, Mercedes, Gutiérrez-Rodríguez, Marta, and Valenzuela, Carmen
- Abstract
The transient outward potassium current (Itof) is generated by the activation of KV4 chan- nels 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 KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/KChIP2/KCNE2 channels. CHO cells were transiently transfected with cDNAs codifying for different proteins (KV4.3/KChIP2, KV4.3/KChIP2/DPP6 or KV4.3/KChIP2/KCNE2), and the potassium currents were recorded using the whole-cell patch-clamp technique. IQM-266 decreased the maximum peak of KV4.3/KChIP2, KV4.3/KChIP2/DPP6 and KV4.3/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 KV4.3/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 applica- tion of trains of pulses to cells expressing KV4.3/KChIP2 and KV4.3/KChIP2/KCNE2, but not in KV4.3/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 KV4.3/KChIP2 channels to IQM-266.
- Published
- 2022