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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F21%3A00543856" target="_blank" >RIV/67985823:_____/21:00543856 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1038/s41467-021-23024-z" target="_blank" >https://doi.org/10.1038/s41467-021-23024-z</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-021-23024-z" target="_blank" >10.1038/s41467-021-23024-z</a>

Result language

angličtina

Original language name

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

Original language description

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. N-Methyl-D-aspartate receptors (NMDARs) activation involves closure of the GluN1 and GluN2 subunit ligand binding domains, which is regulated allosterically by the amino-terminal domain (ATD). Here, smFRET, used to monitor conformational rearrangements of the NMDAR ATD, reveals that glutamate binding to GluN2 subunits elicits two identical, sequential steps of ATD dimer separation that are regulated by protons.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

30103 - Neurosciences (including psychophysiology)

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Nature Communications

ISSN

2041-1723

e-ISSN

2041-1723

Volume of the periodical

12

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

10

Pages from-to

2694

UT code for WoS article

000658724200009

EID of the result in the Scopus database

2-s2.0-85105768935