title: 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 Ca(2+) 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.
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia; School of Mathematics and Physics, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Brendan A
authors.initials: BA
authors.lastname: Bicknell
authors.affiliation: Queensland Brain Institute, The University of Queensland, St. Lucia, QLD 4072, Australia; School of Mathematics and Physics, The University of Queensland, St. Lucia, QLD 4072, Australia g.goodhill@uq.edu.au.
authors.forename: Geoffrey J
authors.identifier: 0000-0001-9789-9355
authors.initials: GJ
authors.lastname: Goodhill
mesh_terms: D055592:Biophysical Phenomena; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry*; D007473:Ion Channels / Q000737:chemistry*; D007700:Kinetics; D058446:Ligand-Gated Ion Channels; D008024:Ligands; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D007473:Ion Channels; D058446:Ligand-Gated Ion Channels; D008024:Ligands; D002118:Calcium
keywords: Markov model; calcium signaling; inositol 1,4,5-trisphosphate receptor; ion channel; modal gating