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

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1520-1532.e15
JournalCell
Volume175
Issue number6
DOIs
StatePublished - Nov 29 2018

Fingerprint

N-Methyl-D-Aspartate Receptors
Protons
Zinc
Ion Channels
Constriction
Cryoelectron Microscopy
Neuronal Plasticity
Inhibition (Psychology)
Modulators
Plasticity
Conformations
Brain
Schizophrenia
Microscopic examination
Ischemia
Modulation
Ions
Ligands
Data storage equipment

Keywords

  • allosteric modulation
  • glutamate receptor
  • ligand-gated ion channel
  • neurotransmitter receptor
  • proton-inhibition
  • structural biology
  • synapse
  • zinc-inhibition

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor. / Jalali-Yazdi, Farzad; Chowdhury, Sandipan; Yoshioka, Craig; Gouaux, Eric.

In: Cell, Vol. 175, No. 6, 29.11.2018, p. 1520-1532.e15.

Research output: Contribution to journalArticle

Jalali-Yazdi, Farzad ; Chowdhury, Sandipan ; Yoshioka, Craig ; Gouaux, Eric. / Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor. In: Cell. 2018 ; Vol. 175, No. 6. pp. 1520-1532.e15.
@article{86b770f2093e413bbc3a3c178631a45f,
title = "Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor",
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. 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.",
keywords = "allosteric modulation, glutamate receptor, ligand-gated ion channel, neurotransmitter receptor, proton-inhibition, structural biology, synapse, zinc-inhibition",
author = "Farzad Jalali-Yazdi and Sandipan Chowdhury and Craig Yoshioka and Eric Gouaux",
year = "2018",
month = "11",
day = "29",
doi = "10.1016/j.cell.2018.10.043",
language = "English (US)",
volume = "175",
pages = "1520--1532.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - Mechanisms for Zinc and Proton Inhibition of the GluN1/GluN2A NMDA Receptor

AU - Jalali-Yazdi, Farzad

AU - Chowdhury, Sandipan

AU - Yoshioka, Craig

AU - Gouaux, Eric

PY - 2018/11/29

Y1 - 2018/11/29

N2 - 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. 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.

AB - 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. 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.

KW - allosteric modulation

KW - glutamate receptor

KW - ligand-gated ion channel

KW - neurotransmitter receptor

KW - proton-inhibition

KW - structural biology

KW - synapse

KW - zinc-inhibition

UR - http://www.scopus.com/inward/record.url?scp=85056877808&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85056877808&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2018.10.043

DO - 10.1016/j.cell.2018.10.043

M3 - Article

VL - 175

SP - 1520-1532.e15

JO - Cell

JF - Cell

SN - 0092-8674

IS - 6

ER -