Kv4 channels exhibit modulation of closed-state inactivation in inside-outpatches

The mechanisms of inactivation gating of the neuronal somatodendritic A-typ e K+ current and the cardiac I-to were investigated in Xenopus oocyte macro patches expressing Kv4.1 and Kv4.3 channels. Upon membrane patch excision ( inside-out), Kv4.1 channels undergo time-dependent acceleration of macrosco pic inactivation accompanied by a parallel partial current rundown. These c hanges are readily reversible by patch cramming, suggesting the influence o f modulatory cytoplasmic factors. The consequences of these perturbations w ere investigated in detail to gain insights into the biophysical basis and mechanisms of inactivation gating. Accelerated inactivation at positive vol tages (0 to +110 mV) is mainly the result of reducing the time constant of slow inactivation and the relative weight of the slow component of inactiva tion. Concomitantly, the time constants of closed-state inactivation at neg ative membrane potentials (-90 to -50 mV) are substantially decreased in in side-out patches. Deactivation is moderately accelerated, and recovery from inactivation and the peak G-V curve exhibit little or no change. In agreem ent with more favorable closed-state inactivation in inside-out patches, th e steady-state inactivation curve exhibits a hyperpolarizing shift of simil ar to 10 mV. Closed-state inactivation was similarly enhanced in Kv4.3. An allosteric model that assumes significant closed-state inactivation at all relevant voltages can explain Kv4 inactivation gating and the modulatory ch anges.