Emergence of ion channel modal gating from independent subunit kinetics

Abstract

Many ion channels exhibit a slow stochastic switching between distinct modes of gating activity. This feature of channel behavior has pronounced implications for the dynamics of ionic currents and the signaling pathways that they regulate. A canonical example is the inositol 1,4,5-trisphosphate receptor (IP3R) channel, whose regulation of intracellular Ca2+ concentration is essential for numerous cellular processes. However, the underlying biophysical mechanisms that give rise to modal gating in this and most other channels remain unknown. Although ion channels are composed of protein subunits, previous mathematical models of modal gating are coarse grained at the level of whole-channel states, limiting further dialogue between theory and experiment. Here we propose an origin for modal gating, by modeling the kinetics of ligand binding and conformational change in the IP3R at the subunit level. We find good agreement with experimental data over a wide range of ligand concentrations, accounting for equilibrium channel properties, transient responses to changing ligand conditions, and modal gating statistics. We show how this can be understood within a simple analytical framework and confirm our results with stochastic simulations. The model assumes that channel subunits are independent, demonstrating that cooperative binding or concerted conformational changes are not required for modal gating. Moreover, the model embodies a generally applicable principle: If a timescale separation exists in the kinetics of individual subunits, then modal gating can arise as an emergent property of channel behavior.

Modulation of KV7 Channel Deactivation by PI(4,5)P2

“…This suggests that K V 7.2/K V 7.3 channels in their second mode of activity are more sensitive to PI(4,5)P 2 depletion. Modal gating has been documented in the activity of many types of channels and it has been shown to be critically involved in their function (Nilius, 1988;Marrion, 1993;Naranjo and Brehm, 1993;Zahradnikova and Zahradnik, 1995;Zahradnikova et al, 1999;Magleby, 2004;Tanskanen et al, 2005;Chakrapani et al, 2011;Bicknell and Goodhill, 2016). To understand modal gating, it is essential to define what a "mode" is.…”

“…For RyR2, KcsA, and some neuronal receptors such acetylcholine and NMDA receptors that undergo desensitization (Nilius, 1988;Magleby, 2004;Bicknell and Goodhill, 2016), modal gating is correlated with the decrease of channel activity as activation is prolonged. However, this is not the case in K V 7 channels.…”

NMDA receptors: linking physiological output to biophysical operation

“…Further, for heterogeneous portions in the record to reflect a true mode shift, the recorded signal must originate from the same channel thus requiring recordings from one-channel patches. Despite these impediments, evidence is accumulating that modal gating is a universal property of ion channels that shapes their functional output and is biologically regulated 90–92 .…”

Shifts in the selectivity filter dynamics cause modal gating in K+ channels

“…Indeed, electrophysiological measurements showed that point-mutations at E71 lock the KcsA channel into different, natively occurring gating modes, which are best represented by a high-open probability (E71A), a low-open probability (E71I), and a high-frequency flicker (E71Q) mode 6 . Random shifts between such gating modes, known as modal gating shifts, were observed in various eukaryotic and prokaryotic K + channels, and are a widespread regulatory mechanism of channel activity 4,7–11 . Yet, despite their broad functional importance, the structural correlates and triggers of modal gating shifts are unknown.…”