Bi-Directional Allosteric Pathway in NMDA Receptor Activation and Modulation

Authors

Paula A Bender
Subhajit Chakraborty
Ryan J Durham
Vladimir Berka
Elisa Carrillo
Vasanthi Jayaraman

Publication Date

10-13-2024

Journal

Nature Communications

Abstract

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane segments inversely correlate with those observed at the amino-terminal domain, confirming direct allosteric communication between these domains. Additionally, binding of a positive allosteric modulator at the transmembrane domain shifts the conformational profile of the amino-terminal domain towards the active state, revealing a bidirectional allosteric pathway between extracellular and transmembrane domains.

Keywords

Receptors, N-Methyl-D-Aspartate, Allosteric Regulation, Humans, Fluorescence Resonance Energy Transfer, HEK293 Cells, Animals, Protein Domains, Protein Conformation, Protein Binding, Ligands, Ion channels in the nervous system, Ion transport, Ion channels

DOI

10.1038/s41467-024-53181-w

PMID

39396999

PMCID

PMC11471786

PubMedCentral® Posted Date

10-13-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes