KV1.2 channels inactivate through a mechanism similar to C-type inactivation

Abstract

C-type inactivation has been described in multiple voltage-gated K+ channels and in great detail in the Drosophila Shaker channel. As channels have moved into the structural era, atomic details of this and other gating mechanisms have started to be better understood. To date, the only voltage-gated channels whose structure has been solved are KvAP (X-ray diffraction), the KV1.2- KV2.1 \"paddle\" chimera (X-ray diffraction), KV1.2 (Cryo-EM); and ether-a-go-go (Cryo-EM) (Wang and MacKinnon, 2017), however, the characteristics and mechanisms of slow inactivation in these channels are unknown or poorly characterized. Here we present a detailed study of slow inactivation in the rat KV1.2 and show that it has some properties consistent with the C-type inactivation described in Shaker. We also study the effects of some mutations that are known to modulate C-type inactivation in Shaker and show that qualitative and quantitative differences exist in their functional effects, possibly underscoring subtle but important structural differences between the C-inactivated states in Shaker and KV1.2.