title: Mechanism of the modulation of Kv4:KChIP-1 channels by external K+.
abstract: In response to a prolonged membrane depolarization, inactivation autoregulates the activity of voltage-gated ion channels. Slow inactivation involving a localized constriction of the selectivity filter (P/C-type mechanism) is prevalent in many voltage-gated K(+) channels of the Kv1 subfamily. However, the generalization of this mechanism to other Kv channel subfamilies has remained uncertain and controversial. In agreement with a "foot-in-the-door" mechanism and the presence of ion-ion interactions in the pore, elevated external K(+) slows the development of P/C-type inactivation and accelerates its recovery. In sharp contrast and resembling the regulation of the hippocampal A-type K(+) current, we found that Kv4.x channels associated with KChIP-1 (an auxiliary subunit) exhibit accelerated inactivation and unaffected recovery from inactivation when exposed to elevated external K(+). This regulation depends on the ability of a permeant ion to enter the selectivity filter (K(+) = Rb(+) = NH4(+) > Cs(+) > Na(+)); and the apparent equilibrium dissociation constant of a single regulatory site is 8 mM for K(+). By applying a robust quantitative global kinetic modeling approach to all macroscopic properties over a 210-mV range of membrane potentials, we determined that elevated external K(+) inhibits unstable closed states outside the main activation pathway and thereby promotes preferential closed-state inactivation. These results suggest the presence of a vestigial and unstable P/C-type mechanism of inactivation in Kv4 channels and strengthen the concept of novel mechanisms of closed-state inactivation. Regulation of Kv4 channel inactivation by hyperkalemia may help to explain the pathophysiology of electrolyte imbalances in excitable tissues.
authors.affiliation: Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Yu A
authors.initials: YA
authors.lastname: Kaulin
authors.forename: J A
authors.initials: JA
authors.lastname: De Santiago-Castillo
authors.forename: C A
authors.initials: CA
authors.lastname: Rocha
authors.forename: M
authors.initials: M
authors.lastname: Covarrubias
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D008956:Models, Chemical; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000008:administration & dosage*; D051672:Shal Potassium Channels / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: D051672:Shal Potassium Channels; D011188:Potassium