Bi-directional allosteric pathway in NMDA receptor activation and modulation

Paula A. Bender, Subhajit Chakraborty, Ryan J. Durham, Vladimir Berka, Elisa Carrillo and Vasanthi Jayaraman ()
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Paula A. Bender: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences
Subhajit Chakraborty: University of Texas Health Science Center at Houston
Ryan J. Durham: University of Texas Health Science Center at Houston
Vladimir Berka: University of Texas Health Science Center at Houston
Elisa Carrillo: University of Texas Health Science Center at Houston
Vasanthi Jayaraman: The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53181-w

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