Modulation of K(V)4.3-KChIP2 Channels by IQM-266: Role of DPP6 and KCNE2

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.