The Activation Gate and Gating Mechanism of the NMDA Receptor

Chang, Huai-Ren; Kuo, Chung‐Chin

doi:10.1523/jneurosci.3485-07.2008

Cited by 82 publications

(94 citation statements)

References 50 publications

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“…That glycine substitution in the GluA2 pore improved ligand-mediated activation suggests that a more flexible M3 has improved function, but may be physiologically unfavorable due to significant basal activity. A previous study showed that substitutions at a corresponding position on NMDA receptors can also affect their channel gating, but the hinging mechanism was not explicitly tested (13). Three possible effects of glycine replacements in the M3 helix may explain their functional consequences.…”

Section: Dmentioning

confidence: 99%

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A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor

Moore

Mirshahi

Ebersole

et al. 2013

Journal of Biological Chemistry

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Background: Ligand binding to ionotropic glutamate receptors opens the channel gate to control synaptic activity. Results: Placing glycine residues at pore-facing positions in the M3 domain of GluA2 confers a more readily activated channel. Conclusion: Like potassium channels, GluA2 uses bending of a pore-lining helix to open its gate and conduct ions. Significance: Flexibility of M3 domain in iGluRs is critical to their function.

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Section: Dmentioning

confidence: 99%

“…Cysteine substitutions in this motif can alter channel activity after modification with MTS reagents (13). Whereas a previous study suggested that iGluRs do not use a hinge for their gating (14), structural information for any fulllength iGluR was not available for those studies, and glycines were the only residues considered as a potential hinge.…”

mentioning

confidence: 97%

A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor

Moore

Mirshahi

Ebersole

et al. 2013

Journal of Biological Chemistry

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“…It is formed by the second half of the transmembrane M3 segment, a region that contains the most highly conserved motif (SYTANLAAF) among all iGluR subunits Chang and Kuo 2008). In the GluA2 structure (captured in a closed state) (Sobolevsky et al 2009), the four M3 helices cross at the level of this conserved motif, thus forming a tight steric closure of the ion conduction pathway.…”

Section: Agonist Recognitionmentioning

confidence: 99%

Synaptic Neurotransmitter-Gated Receptors

Smart

Paoletti

2012

Cold Spring Harbor Perspectives in Biology

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Since the discovery of the major excitatory and inhibitory neurotransmitters and their receptors in the brain, many have deliberated over their likely structures and how these may relate to function. This was initially satisfied by the determination of the first amino acid sequences of the Cys-loop receptors that recognized acetylcholine, serotonin, GABA, and glycine, followed later by similar determinations for the glutamate receptors, comprising non-NMDA and NMDA subtypes. The last decade has seen a rapid advance resulting in the first structures of Cys-loop receptors, related bacterial and molluscan homologs, and glutamate receptors, determined down to atomic resolution. This now provides a basis for determining not just the complete structures of these important receptor classes, but also for understanding how various domains and residues interact during agonist binding, receptor activation, and channel opening, including allosteric modulation. This article reviews our current understanding of these mechanisms for the Cys-loop and glutamate receptor families.T o understand how neurons communicate with each other requires a fundamental understanding of neurotransmitter receptor structure and function. Neurotransmitter-gated ion channels, also known as ionotropic receptors, are responsible for fast synaptic transmission. They decode chemical signals into electrical responses, thereby transmitting information from one neuron to another. Their suitability for this important task relies on their ability to respond very rapidly to the transient release of neurotransmitter to affect cell excitability.In the central nervous system (CNS), fast synaptic transmission results in two main effects: neuronal excitation and inhibition. For excitation, the principal neurotransmitter involved is glutamate, which interacts with ionotropic (integral ion channel) and metabotropic (secondmessenger signaling) receptors. The ionotropic glutamate receptors are permeable to cations, which directly cause excitation. Acetylcholine and serotonin can also activate specific cationselective ionotropic receptors to affect neuronal excitation. For controlling cell excitability, inhibition is important, and this is mediated by the neurotransmitters GABA and glycine, causing an increased flux of anions. GABA predominates as the major inhibitory transmitter throughout

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“…Further evidence for subunit-specific contributions is provided by the observation that the Lurcher mutation (A / T in the underlined position of SYTANLAAF) in GluN1 significantly slowed down channel deactivation and desensitization (23), implicating a much stronger ability of this mutation in GluN1 than the counterpart in GluN2A in maintaining channel opening. The studies by Wollmuth and co-workers (19,20,22,24) and by others (25)(26)(27)(28) reported state-dependent modification rates of cysteines introduced around the extracellular vestibule, which could possibly indicate movements of the constituent segments during channel activation. However, without an atomic model for the open state, the ability to interpret these data is limited.…”

Section: Introductionmentioning

confidence: 96%

An NMDA Receptor Gating Mechanism Developed from MD Simulations Reveals Molecular Details Underlying Subunit-Specific Contributions

Dai

Zhou

2013

Biophysical Journal

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N-methyl-D-aspartate (NMDA) receptors are obligate heterotetrameric ligand-gated ion channels that play critical roles in learning and memory. Here, using targeted molecular dynamics simulations, we developed an atomistic model for the gating of the GluN1/GluN2A NMDA receptor. Upon agonist binding, lobe closure of the ligand-binding domain produced outward pulling of the M3-D2 linkers, leading to outward movements of the C-termini of the pore-lining M3 helices and opening of the channel. The GluN2A subunits, similar to the distal (B/D) subunits in the homotetrameric GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate receptor, had greater M3 outward movements and thus contributed more to channel gating than the GluN1 subunits. Our gating model is validated by functional studies, including cysteine modification data indicating wider accessibility to the GluN1 M3 helices than to the GluN2A M3 helices from the lumen of the open channel, and reveals why the Lurcher mutation in GluN1 has a stronger ability in maintaining channel opening than the counterpart in GluN2A. The resulting structural model for the open state provides an explanation for the Ca(2+) permeability of NMDA receptors, and the structural differences between the closed and open states form the basis for drug design.

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The Activation Gate and Gating Mechanism of the NMDA Receptor

Cited by 82 publications

References 50 publications

A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor

A Conserved Mechanism for Gating in an Ionotropic Glutamate Receptor

Synaptic Neurotransmitter-Gated Receptors

An NMDA Receptor Gating Mechanism Developed from MD Simulations Reveals Molecular Details Underlying Subunit-Specific Contributions

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