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.

Structural Insights into KChIP4a Modulation of Kv4.3 Inactivation

“…It has been reported that deletion of the Kv4 N terminus, which induces fast inactivation presumably by pore occlusion, results in slower inactivation (30,34). Sequestering the proximal N terminus of Kv4, KChIPs also gives to rise to slow inactivation of the channel (27,42). All of these findings suggest that inactivation of Kv4 channels is also likely to be mediated by other mechanisms such as closed-state inactivation (43).…”

Kv3.4 channel function and dysfunction in nociceptors

“…IChMASCOT was used as previously described [35][36][37] to obtain the best global fit of a Markov kinetic model to DRG nociceptor Kv3.4 currents. The global fit involves the simultaneous fitting of multiple voltage and time dependent current properties.…”

The "structurally minimal" isoform KChIP2d modulates recovery of Kv4.3 N-terminal deletion mutant <meta charset="utf-8" /> <span class="s2">Δ</span>2-39

“…[1][2][3] Unlike other much more well-studied potassium channels, such as Shaker [4][5][6] and KcsA, In a recent issue of Channels we presented results 14 on the K v 4.3 partial N-terminal deletion mutant D2-39 (which removes amino acids 2-39 of the proximal N-terminal domain). In contrast to predictions of popular K v 4 gating models, 2,[9][10][11][12] our D2-39 analysis 14 yielded several unexpected results, among which the following two were possibly the most surprising: i) partial N-terminal deletion not only removed the prominent rapid component of macroscopic inactivation, but also slowed the net rate of recovery from inactivation; and ii) coexpression of KChiP 2b (K Channel interacting Protein 2b) 1,3,15 while having no major effect on the rate of D2-39 macroscopic inactivation, produced significant acceleration of the rate of D2-39 recovery. The first result (which is generally consistent with previous K v 4…”

“…1, inset). Beginning at an interpulse interval of Dt = 60 msec (so as to "bypass" this initial complication of sigmoidicity 14 ), the constrained exponential best fit to the mean D2-39 + KChIP 2d data points resulted in an estimated recovery time constant (trec = 120 msec) that was very similar to that of D2-39 + KChiP studies 2,[9][10][11][12] indicates that deletion of the K v 4.3 proximal N-terminal, while mimicking the slowing effect of KChIP 2b on macroscopic inactivation, [15][16][17] does not mimic the acceleratory effects of KChIP 2b on recovery. The second result (which is in contrast to previous K v 4.2 studies 2,10,11 ) indicates that an intact N-terminal proximal domain is not obligatory for KChIP2 isoforms to exert acceleratory effects upon K v 4 channel recovery.…”