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Gating Motions and Stationary Gating Properties of Ionotropic Glutamate Receptors

Title: Gating Motions and Stationary Gating Properties of Ionotropic Glutamate Receptors: Computation Meets Electrophysiology.
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Name(s): Zhou, Huan-Xiang, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2017-04-18
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Ionotropic glutamate receptors (iGluRs) are tetrameric ligand-gated ion channels essential to all aspects of brain function, including higher order processes such as learning and memory. For decades, electrophysiology was the primary means for characterizing the function of iGluRs and gaining mechanistic insight. Since the turn of the century, structures of isolated water-soluble domains and transmembrane-domain-containing constructs have provided the basis for formulating mechanistic hypotheses. Because these structures only represent sparse, often incomplete snapshots during iGluR activation, significant gaps in knowledge remain regarding structures, energetics, and dynamics of key substates along the functional processes. Some of these gaps have recently been filled by molecular dynamics simulations and theoretical modeling. In this Account, I describe our work in the latter arena toward characterizing iGluR gating motions and developing a formalism for calculating thermodynamic and kinetic properties of stationary gating. The structures of iGluR subunits have a highly modular architecture, in which the ligand-binding domain and the transmembrane domain are well separated and connected by flexible linkers. The ligand-binding domain in turn is composed of two subdomains. During activation, agonist binding induces the closure of the intersubdomain cleft. The cleft closure leads to the outward pulling of a linker tethered to the extracellular terminus of the major pore-lining helix of the transmembrane domain, thereby opening the channel. This activation model based on molecular dynamics simulations was validated by residue-specific information from electrophysiological data on cysteine mutants. A further critical test was made through introducing glycine insertions in the linker. Molecular dynamics simulations showed that, with lengthening by glycine insertions, the linker became less effective in pulling the pore-lining helix, leading to weaker stabilization of the channel-open state. In full agreement, single-channel recordings showed that the channel open probability decreased progressively as the linker was lengthened by glycine insertions. Crystal structures of ligand-binding domains showing different degrees of cleft closure between full and partial agonists suggested a simple mechanism for one subtype of iGluRs, but mysteries surrounded a second subtype, where the ligand-binding domains open to similar degrees when bound with either full or partial agonists. Our free energy simulations now suggest that broadening of the free energy basin for cleft closure is a plausible solution. A theoretical basis for these mechanistic hypotheses on partial agonisms was provided by a model for the free energy surface of a full receptor, where the stabilization by cleft closure is transmitted via the linker to the channel-open state. This model can be implemented by molecular dynamics simulations to predict thermodynamic and kinetics properties of stationary gating that are amenable to direct test by single-channel recordings. Close integration between computation and electrophysiology holds great promises in revealing the conformations of key substates in functional processes and the mechanisms of disease-associated mutations.
Identifier: FSU_pmch_28186717 (IID), 10.1021/acs.accounts.6b00598 (DOI), PMC5398286 (PMCID), 28186717 (RID), 28186717 (EID)
Grant Number: R01 GM058187, R35 GM118091
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5398286.
Subject(s): Electrophysiological Phenomena
Humans
Kinetics
Molecular Dynamics Simulation
Receptors, Ionotropic Glutamate/chemistry
Receptors, Ionotropic Glutamate/metabolism
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_28186717
Host Institution: FSU
Is Part Of: Accounts of chemical research.
1520-4898
Issue: iss. 4, vol. 50

Choose the citation style.
Zhou, H. -X. (2017). Gating Motions and Stationary Gating Properties of Ionotropic Glutamate Receptors: Computation Meets Electrophysiology. Accounts Of Chemical Research. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_28186717