Emergence of ion channel modal gating from independent subunit kinetics

Bicknell, Brendan A. and Goodhill, Geoffrey J. (2016) Emergence of ion channel modal gating from independent subunit kinetics. Proceedings of the National Academy of Sciences, 113 36: E5288-E5297. doi:10.1073/pnas.1604090113

Author Bicknell, Brendan A.
Goodhill, Geoffrey J.
Title Emergence of ion channel modal gating from independent subunit kinetics
Journal name Proceedings of the National Academy of Sciences   Check publisher's open access policy
ISSN 1091-6490
Publication date 2016-09-06
Sub-type Article (original research)
DOI 10.1073/pnas.1604090113
Open Access Status Not yet assessed
Volume 113
Issue 36
Start page E5288
End page E5297
Total pages 10
Place of publication Washington, DC, United States
Publisher National Academy of Sciences
Language eng
Formatted 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.
Keyword Ion channel
Modal gating
Inositol 1,4,5-trisphosphate receptor
Markov model
Calcium signaling
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: School of Mathematics and Physics
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Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 6 times in Thomson Reuters Web of Science Article | Citations
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