The Link between Ion Permeation and Inactivation Gating of Kv4 Potassium Channels

Abstract

Kv4 potassium channels undergo rapid inactivation but do not seem to exhibit the classical N-type and C-type mechanisms present in other Kv channels. We have previously hypothesized that Kv4 channels preferentially inactivate from the preopen closed state, which involves regions of the channel that contribute to the internal vestibule of the pore. To further test this hypothesis, we have examined the effects of permeant ions on gating of three Kv4 channels (Kv4.1, Kv4.2, and Kv4.3) expressed in Xenopus oocytes. Rb + is an excellent tool for this purpose because its prolonged residency time in the pore delays K + channel closing. The data showed that, only when Rb + carried the current, both channel closing and the development of macroscopic inactivation are slowed (1.5- to 4-fold, relative to the K + current). Furthermore, macroscopic Rb + currents were larger than K + currents (1.2- to 3-fold) as the result of a more stable open state, which increases the maximum open probability. These results demonstrate that pore occupancy can influence inactivation gating in a manner that depends on how channel closing impacts inactivation from the preopen closed state. By examining possible changes in ionic selectivity and the influence of elevating the external K + concentration, additional experiments did not support the presence of C-type inactivation in Kv4 channels.