Excitatory and inhibitory D-serine binding to the NMDA receptor

Yovanno, Remy A, Chou, Tsung Han, Brantley, Sarah J, Furukawa, Hiro, Lau, Albert Y (October 2022) Excitatory and inhibitory D-serine binding to the NMDA receptor. eLife, 11. e77645. ISSN 2050-084X

[thumbnail of Excitatory and inhibitory D-serine binding to the NMDA receptor.pdf] PDF
Excitatory and inhibitory D-serine binding to the NMDA receptor.pdf
Available under License Creative Commons Attribution.

Download (11MB)
URL: https://www.ncbi.nlm.nih.gov/pubmed/36301074
DOI: 10.7554/eLife.77645

Abstract

N-methyl-D-aspartate receptors (NMDARs) uniquely require binding of two different neurotransmitter agonists for synaptic transmission. D-serine and glycine bind to one subunit, GluN1, while glutamate binds to the other, GluN2. These agonists bind to the receptor's bi-lobed ligand-binding domains (LBDs), which close around the agonist during receptor activation. To better understand the unexplored mechanisms by which D-serine contributes to receptor activation, we performed multi-microsecond molecular dynamics simulations of the GluN1/GluN2A LBD dimer with free D-serine and glutamate agonists. Surprisingly, we observed D-serine binding to both GluN1 and GluN2A LBDs, suggesting that D-serine competes with glutamate for binding to GluN2A. This mechanism is confirmed by our electrophysiology experiments, which show that D-serine is indeed inhibitory at high concentrations. Although free energy calculations indicate that D-serine stabilizes the closed GluN2A LBD, its inhibitory behavior suggests that it either does not remain bound long enough or does not generate sufficient force for ion channel gating. We developed a workflow using pathway similarity analysis to identify groups of residues working together to promote binding. These conformation-dependent pathways were not significantly impacted by the presence of N-linked glycans, which act primarily by interacting with the LBD bottom lobe to stabilize the closed LBD.

Item Type: Paper
Subjects: bioinformatics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor
bioinformatics > genomics and proteomics > small molecules > NMDA receptor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions
organs, tissues, organelles, cell types and functions > cell types and functions
bioinformatics > genomics and proteomics > small molecules > Glutamate
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > neurotransmitter
organs, tissues, organelles, cell types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > small molecules
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > synaptic transmission
CSHL Authors:
Communities: CSHL labs > Furukawa lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 27 October 2022
Date Deposited: 08 Nov 2022 17:35
Last Modified: 17 Jan 2024 19:36
PMCID: PMC9612912
URI: https://repository.cshl.edu/id/eprint/40749

Actions (login required)

Administrator's edit/view item Administrator's edit/view item
CSHL HomeAbout CSHLResearchEducationNews & FeaturesCampus & Public EventsCareersGiving