Subtype-specific conformational landscape of NMDA receptor gating

Julia Bleier; Philipe Ribeiro Furtado de Mendonca; Chris H. Habrian; Cherise Stanley; Vojtech Vyklicky; Ehud Y. Isacoff

Cell Reports (Aug 2024)

Subtype-specific conformational landscape of NMDA receptor gating

Julia Bleier,
Philipe Ribeiro Furtado de Mendonca,
Chris H. Habrian,
Cherise Stanley,
Vojtech Vyklicky,
Ehud Y. Isacoff

Affiliations

Julia Bleier: Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA
Philipe Ribeiro Furtado de Mendonca: Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Chris H. Habrian: Biophysics Graduate Group, University of California, Berkeley, Berkeley, CA 94720, USA
Cherise Stanley: Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Vojtech Vyklicky: Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA
Ehud Y. Isacoff: Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Weill Neurohub, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biology & Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; Corresponding author

Journal volume & issue: Vol. 43, no. 8
p. 114634

Abstract

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Summary: N-methyl-D-aspartate receptors are ionotropic glutamate receptors that mediate synaptic transmission and plasticity. Variable GluN2 subunits in diheterotetrameric receptors with identical GluN1 subunits set very different functional properties. To understand this diversity, we use single-molecule fluorescence resonance energy transfer (smFRET) to measure the conformations of the ligand binding domain and modulatory amino-terminal domain of the common GluN1 subunit in receptors with different GluN2 subunits. Our results demonstrate a strong influence of the GluN2 subunits on GluN1 rearrangements, both in non-agonized and partially agonized activation intermediates, which have been elusive to structural analysis, and in the fully liganded state. Chimeric analysis reveals structural determinants that contribute to these subtype differences. Our study provides a framework for understanding the conformational landscape that supports highly divergent levels of activity, desensitization, and agonist potency in receptors with different GluN2s and could open avenues for the development of subtype-specific modulators.

CP: Neuroscience

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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