Bi-directional allosteric pathway in NMDA receptor activation and modulation
Bi-directional allosteric pathway in NMDA receptor activation and modulation
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 utilized 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.
Bender Paula A.、Durham Ryan J.、Berka Vladimir、Chakraborty Subhajit、Jayaraman Vasanthi、Carrillo Elisa
The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences||Department of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at HoustonDepartment of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at HoustonDepartment of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at HoustonDepartment of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at HoustonThe University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences||Department of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at HoustonDepartment of Biochemistry and Molecular Biology, Center for Membrane Biology, University of Texas Health Science Center at Houston
基础医学神经病学、精神病学生物科学研究方法、生物科学研究技术
N-methyl-D-aspartate receptorsNMDARsGluN1GluN2AGluN2Dsingle-molecule FRETallosteric modulationGNE-9278allostery
Bender Paula A.,Durham Ryan J.,Berka Vladimir,Chakraborty Subhajit,Jayaraman Vasanthi,Carrillo Elisa.Bi-directional allosteric pathway in NMDA receptor activation and modulation[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/2024.04.16.589813.点此复制
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