Conformational rearrangement of the NMDA receptor amino-terminal domain during activation and allosteric modulation

Vyklicky, Vojtech; Stanley, Cherise; Habrian, Chris; Isacoff, Ehud Y.

doi:10.1038/s41467-021-23024-z

Conformational rearrangement of the NMDA receptor amino-terminal domain during activation and allosteric modulation

Journal Article · Tue May 11 00:00:00 EDT 2021 · Nature Communications

DOI:https://doi.org/10.1038/s41467-021-23024-z· OSTI ID:1816037

^[1]; Stanley, Cherise ^[2]; Habrian, Chris ^[3]; ^[4]

Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology; Czech Academy of Sciences, Prague (Czech Republic). Inst. of Physiology; OSTI
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology
Univ. of California, Berkeley, CA (United States). Biophysics Graduate Program
Univ. of California, Berkeley, CA (United States). Dept. of Molecular and Cell Biology, Biophysics Graduate Program; Helen Wills Neuroscience Inst.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biology & Integrated Bioimaging Division

N-Methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors essential for synaptic plasticity and memory. Receptor activation involves glycine- and glutamate-stabilized closure of the GluN1 and GluN2 subunit ligand binding domains that is allosterically regulated by the amino-terminal domain (ATD). Using single molecule fluorescence resonance energy transfer (smFRET) to monitor subunit rearrangements in real-time, we observe a stable ATD inter-dimer distance in the Apo state and test the effects of agonists and antagonists. We find that GluN1 and GluN2 have distinct gating functions. Glutamate binding to GluN2 subunits elicits two identical, sequential steps of ATD dimer separation. Glycine binding to GluN1 has no detectable effect, but unlocks the receptor for activation so that glycine and glutamate together drive an altered activation trajectory that is consistent with ATD dimer separation and rotation. We find that protons exert allosteric inhibition by suppressing the glutamate-driven ATD separation steps, and that greater ATD separation translates into greater rotation and higher open probability.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1816037

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 12; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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