Uncoupling of Gating Charge Movement and Closure of the Ion Pore During Recovery from Inactivation in the Kv1.5 Channel

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Abstract
Both wild-type (WT) and nonconducting W472F mutant (NCM) Kv1.5 channels are able to conduct Na+ in their inactivated states when K+ is absent. Replacement of K+ with Na+ or NMG+ allows rapid and complete inactivation in both WT and W472F mutant channels upon depolarization, and on return to negative potentials, transition of inactivated channels to closed-inactivated states is the first step in the recovery of the channels from inactivation. The time constant for immobilized gating charge recovery at −100 mV was 11.1 ± 0.4 ms (n = 10) and increased to 19.0 ± 1.6 ms (n = 3) when NMG+o was replaced by Na+o. However, the decay of the Na+ tail currents through inactivated channels at −100 mV had a time constant of 129 ± 26 ms (n = 18), much slower than the time required for gating charge recovery. Further experiments revealed that the voltage-dependence of gating charge recovery and of the decay of Na+ tail currents did not match over a 60 mV range of repolarization potentials. A faster recovery of gating charge than pore closure was also observed in WT Kv1.5 channels. These results provide evidence that the recovery of the gating elements is uncoupled from that of the pore in Na+-conducting inactivated channels. The dissociation of the gating charge movements and the pore closure could also be observed in the presence of symmetrical Na+ but not symmetrical Cs+. This difference probably stems from the difference in the respective abilities of the two ions to limit inactivation to the P-type state or prevent it altogether.