Excitatory and inhibitory D-serine binding to the NMDA receptor
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 (LB...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/77645 |
| _version_ | 1797989935113830400 |
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| author | Remy A Yovanno Tsung Han Chou Sarah J Brantley Hiro Furukawa Albert Y Lau |
| author_facet | Remy A Yovanno Tsung Han Chou Sarah J Brantley Hiro Furukawa Albert Y Lau |
| author_sort | Remy A Yovanno |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T08:28:26Z |
| format | Article |
| id | doaj.art-eb5619844bf3461594e8352d599b58d6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T08:28:26Z |
| publishDate | 2022-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-eb5619844bf3461594e8352d599b58d62022-12-22T04:34:40ZengeLife Sciences Publications LtdeLife2050-084X2022-10-011110.7554/eLife.77645Excitatory and inhibitory D-serine binding to the NMDA receptorRemy A Yovanno0https://orcid.org/0000-0003-3852-6684Tsung Han Chou1https://orcid.org/0000-0001-6154-6283Sarah J Brantley2Hiro Furukawa3https://orcid.org/0000-0001-8296-8426Albert Y Lau4https://orcid.org/0000-0002-0967-7558Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United StatesW.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, United StatesDepartment of Biology, Johns Hopkins University, Baltimore, United StatesW.M. Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, United StatesDepartment of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, United StatesN-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.https://elifesciences.org/articles/77645NMDA receptorglutamate receptorligand bindingmolecular dynamicselectrophysiology |
| spellingShingle | Remy A Yovanno Tsung Han Chou Sarah J Brantley Hiro Furukawa Albert Y Lau Excitatory and inhibitory D-serine binding to the NMDA receptor eLife NMDA receptor glutamate receptor ligand binding molecular dynamics electrophysiology |
| title | Excitatory and inhibitory D-serine binding to the NMDA receptor |
| title_full | Excitatory and inhibitory D-serine binding to the NMDA receptor |
| title_fullStr | Excitatory and inhibitory D-serine binding to the NMDA receptor |
| title_full_unstemmed | Excitatory and inhibitory D-serine binding to the NMDA receptor |
| title_short | Excitatory and inhibitory D-serine binding to the NMDA receptor |
| title_sort | excitatory and inhibitory d serine binding to the nmda receptor |
| topic | NMDA receptor glutamate receptor ligand binding molecular dynamics electrophysiology |
| url | https://elifesciences.org/articles/77645 |
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