title: Rapid induction of P/C-type inactivation is the mechanism for acid-induced K+ current inhibition.
abstract: 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.
authors.affiliation: Department of Physiology, University of British Columbia, Vancouver V6T 1Z3, Canada.
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
authors.forename: Harley T
authors.initials: HT
authors.lastname: Kurata
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kehl
authors.forename: David
authors.initials: D
authors.lastname: Fedida
mesh_terms: D000143:Acids / Q000378:metabolism*; D002460:Cell Line; D004553:Electric Conductivity; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels / Q000378:metabolism / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels / Q000378:metabolism / Q000502:physiology
chemical_list: D000143:Acids; C496981:KCNA5 protein, human; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels