GluN2A and GluN2B NMDA receptors use distinct allosteric routes

Meilin Tian, David Stroebel, Laura Piot, Mélissa David, Shixin Ye () and Pierre Paoletti ()
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Meilin Tian: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM
David Stroebel: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM
Laura Piot: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM
Mélissa David: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM
Shixin Ye: Unité INSERM U1195, Hôpital de Bicêtre, Université Paris-Saclay
Pierre Paoletti: Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Allostery represents a fundamental mechanism of biological regulation that involves long-range communication between distant protein sites. It also provides a powerful framework for novel therapeutics. NMDA receptors (NMDARs), glutamate-gated ionotropic receptors that play central roles in synapse maturation and plasticity, are prototypical allosteric machines harboring large extracellular N-terminal domains (NTDs) that provide allosteric control of key receptor properties with impact on cognition and behavior. It is commonly thought that GluN2A and GluN2B receptors, the two predominant NMDAR subtypes in the adult brain, share similar allosteric transitions. Here, combining functional and structural interrogation, we reveal that GluN2A and GluN2B receptors utilize different long-distance allosteric mechanisms involving distinct subunit-subunit interfaces and molecular rearrangements. NMDARs have thus evolved multiple levels of subunit-specific allosteric control over their transmembrane ion channel pore. Our results uncover an unsuspected diversity in NMDAR molecular mechanisms with important implications for receptor physiology and precision drug development.

Date: 2021
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DOI: 10.1038/s41467-021-25058-9

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