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Structural Mechanisms of Gating in Ionotropic Glutamate Receptors.

ABSTRACT: Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the central nervous system. iGluRs open their ion channels in response to binding of the neurotransmitter glutamate, rapidly depolarize the postsynaptic neuronal membrane, and initiate signal transduction. Recent studies using X-ray crystallography and cryo-electron microscopy have determined full-length iGluR structures that (1) uncover the receptor architecture in an unliganded, resting state, (2) reveal conformational changes produced by ligands in order to activate iGluRs, open their ion channels, and conduct ions, and (3) show how activated, glutamate-bound iGluRs can adopt a nonconducting desensitized state. These new findings, combined with the results of previous structural and functional experiments, kinetic and molecular modeling, mutagenesis, and biochemical analyses, provide new views on the structural mechanisms of iGluR gating.

SUBMITTER: Twomey EC

PROVIDER: S-EPMC5780838 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Structural Mechanisms of Gating in Ionotropic Glutamate Receptors.

Twomey Edward C EC Sobolevsky Alexander I AI

Biochemistry 20171027 3

Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the majority of excitatory neurotransmission in the central nervous system. iGluRs open their ion channels in response to binding of the neurotransmitter glutamate, rapidly depolarize the postsynaptic neuronal membrane, and initiate signal transduction. Recent studies using X-ray crystallography and cryo-electron microscopy have determined full-length iGluR structures that (1) uncover the receptor architecture in ...[more]

PMID: 29037031

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Project 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.

Dataset Information

Structural Mechanisms of Gating in Ionotropic Glutamate Receptors.

Publications

Structural Mechanisms of Gating in Ionotropic Glutamate Receptors.

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