Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor

Farzad Jalali-Yazdi; Sandipan Chowdhury; Craig Yoshioka; Eric Gouaux

doi:10.1016/j.cell.2018.10.043

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Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor

Journal article

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Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor

Farzad Jalali-Yazdi, Sandipan Chowdhury, Craig Yoshioka and Eric Gouaux

Cell, Vol.175(6), pp.1520-1532.e15

11/29/2018

DOI: 10.1016/j.cell.2018.10.043

PMCID: PMC6333211

PMID: 30500536

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Abstract

N-methyl-D-aspartate receptors (NMDARs) play essential roles in memory formation, neuronal plasticity, and brain development, with their dysfunction linked to a range of disorders from ischemia to schizophrenia. Zinc and pH are physiological allosteric modulators of NMDARs, with GluN2A-containing receptors inhibited by nanomolar concentrations of divalent zinc and by excursions to low pH. Despite the widespread importance of zinc and proton modulation of NMDARs, the molecular mechanism by which these ions modulate receptor activity has proven elusive. Here, we use cryoelectron microscopy to elucidate the structure of the GluN1/GluN2A NMDAR in a large ensemble of conformations under a range of physiologically relevant zinc and proton concentrations. We show how zinc binding to the amino terminal domain elicits structural changes that are transduced though the ligand-binding domain and result in constriction of the ion channel gate. [Display omitted] •Cryo-EM structure of the diheteromeric GluN1/GluN2A NMDA receptor•Receptor populates multiple structural states dependent upon zinc concentration and pH•Zinc-induced closure of ATD clamshells propagated to LBD layer and to ion channel gate•Rupture of LBD D1-D1 interface uncouples agonist binding from ion channel gating Cryo-EM structures of the full-length GluN1/GluN2A diheteromeric receptor across a range of physiologically relevant zinc and proton concentrations illustrates how zinc binding elicits structural changes that result in constriction of the ion channel gate.

allosteric modulation

glutamate receptor

ligand-gated ion channel

neurotransmitter receptor

proton-inhibition

structural biology

synapse

zinc-inhibition

Details

Title: Subtitle: Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor
Creators: Farzad Jalali-Yazdi - Vollum Institute
Sandipan Chowdhury - Vollum Institute
Craig Yoshioka - Vollum Institute
Eric Gouaux - Vollum Institute
Resource Type: Journal article
Publication Details: Cell, Vol.175(6), pp.1520-1532.e15
DOI: 10.1016/j.cell.2018.10.043
PMID: 30500536
PMCID: PMC6333211
NLM abbreviation: Cell
ISSN: 0092-8674
eISSN: 1097-4172
Publisher: Elsevier Inc
Grant note: DOI: 10.13039/100000002, name: NIH, award: 1F32MH115595; name: Jane Coffin Childs Fund, award: 61-1591; DOI: 10.13039/100000002, name: NIH, award: R01NS038631
Language: English
Date published: 11/29/2018
Academic Unit: Molecular Physiology and Biophysics
Record Identifier: 9984297597902771

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