KChIP1 splice variants modulate Kv4 channels by promoting P/C-type inactivation features

Kv4 channels mediate a somatodendritic A-type potassium current, which controls neuronal excitability and firing frequency. Kv4 channels form complexes with auxiliary DPPs and KChIPs, which modify channel gating, usually including an acceleration of recovery from inactivation. Although ternary Kv4 + DPP + KChIP complexes represent a likely native channel configuration, little is known about the concerted Kv4 channel modulation by DPPs and KChIPs. Here, we studied the modulatory effects of two functionally distinct KChIP1 splice variants (1a and 1b), utilizing two-electrode voltage-clamp in Xenopus oocytes. We tested Kv4.1, Kv4.2, Kv4.3 S, and Kv4.3 L, co-expressed with either KChIP1 splice variant in binary Kv4 + KChIP1 and ternary Kv4 + DPP + KChIP1 channel configurations. All Kv4.x channels exhibited a second slow component of recovery from inactivation upon co-expression of either KChIP1 splice variant, which persisted in a ternary configuration with DPP. The effect was stronger for KChIP1b, suggesting a functional role of alternative splicing, by limiting fast repetitive availability of the somatodendritic A-type current. Our mechanistic investigations of ternary Kv4.2 + DPP + KChIP1b channels revealed a strong enhancement of P/C-type inactivation features, which are normally vestigial in Kv4 channels, but may co-exist with preferential closed-state inactivation in the presence of KChIP1b.