CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING |
Mechanism of the modulation of Kv4:KChIP-1 channels by external K+
Yuri Kaulin 1*, Jose A. De Santiago-Castillo 1, Carmen Rocha 1 and Manuel Covarrubias 1
1 Thomas Jefferson University
* To whom correspondence should be addressed. E-mail: yuri.kaulin{at}jefferson.edu.
Submitted on August 22, 2007
Revised on September 10, 2007
Accepted on 2 October 2007
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Abstract |
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In response to a prolonged membrane depolarization, inactivation auto-regulates 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.
Key Words:
A-type potassium channel, KChIP, external potassium, global kinetic modeling, hyperkalemia, permeation-gating relationship
