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We studied quinidine block of Kv1.4DeltaN, a K(+) channel lacking N-type inactivation, expressed in Xenopus ooctyes. Initially, quinidine intracellularly blocked the open channel so rapidly it overlapped with activation. This rapid open channel block was reduced (non-additively) by interventions that slow C-type inactivation: [K(+)](o) elevation and an extracellular lysine to tyrosine mutation (K532Y). These manipulations reduced the affinity of rapid open channel block ~10-fold, but left the effective electrical distance unchanged at ~0.15. Following rapid open channel block, there were time-dependent quinidine effects: the rate of inactivation during a single depolarisation was increased, and repetitive pulsing showed use dependence. The rate of recovery from the time-dependent aspect of quinidine block was similar to recovery from normal C-type inactivation. Manipulations that prevented the channel from entering the C-type inactivated state (i.e. high [K(+)](o) or the K532Y mutation) prevented the development of the time-dependent quinidine-induced inactivation. The concentration dependence of the rapid block and the time-dependent quinidine-induced inactivation were similar, but the time-dependent component was strongly voltage sensitive, with an effective electrical distance of 2. Clearly, this cannot reflect the permeation of quinidine through the electric field, but must be the result of some other voltage-sensitive change in the channel. We propose that quinidine promotes the entry of the channel into a C-type inactivated state in a time- and voltage-dependent manner. We developed a mathematical model based on these results to test the hypothesis that, following rapid open channel block, quinidine promotes development of the C-type inactivated state through a voltage-dependent conformational change.
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