Rapid Induction of P/C-type Inactivation Is the Mechanism for Acid-induced K⁺ Current Inhibition

Extracellular acidification is known to decrease the conductance of many voltage-gated potassium channels. In the present study, we investigated the mechanism of H⁺_o-induced current inhibition by taking advantage of Na⁺ permeation through inactivated channels. In hKv1.5, H⁺_o inhibited open-state Na⁺ current with a similar potency to K⁺ current, but had little effect on the amplitude of inactivated-state Na⁺ current. In support of inactivation as the mechanism for the current reduction, Na⁺ current through noninactivating hKv1.5-R487V channels was not affected by [H⁺_o]. At pH 6.4, channels were maximally inactivated as soon as sufficient time was given to allow activation, which suggested two possibilities for the mechanism of action of H⁺_o. These were that inactivation of channels in early closed states occurred while hyperpolarized during exposure to acid pH (closed-state inactivation) and/or inactivation from the open state was greatly accelerated at low pH. The absence of outward Na⁺ currents but the maintained presence of slow Na⁺ tail currents, combined with changes in the Na⁺ tail current time course at pH 6.4, led us to favor the hypothesis that a reduction in the activation energy for the inactivation transition from the open state underlies the inhibition of hKv1.5 Na⁺ current at low pH.