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Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines
Author(s) -
Mony Laetitia,
Zhu Shujia,
Carvalho Stéphanie,
Paoletti Pierre
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.203
Subject(s) - biology , allosteric regulation , nmda receptor , receptor , allosteric modulator , spermine , basis (linear algebra) , modulation (music) , biochemistry , microbiology and biotechnology , neuroscience , biophysics , computational biology , enzyme , philosophy , geometry , mathematics , aesthetics
NMDA receptors (NMDARs) form glutamate‐gated ion channels that have central roles in neuronal communication and plasticity throughout the brain. Dysfunctions of NMDARs are involved in several central nervous system disorders, including stroke, chronic pain and schizophrenia. One hallmark of NMDARs is that their activity can be allosterically regulated by a variety of extracellular small ligands. While much has been learned recently regarding allosteric inhibition of NMDARs, the structural determinants underlying positive allosteric modulation of these receptors remain poorly defined. Here, we show that polyamines, naturally occurring polycations that selectively enhance NMDARs containing the GluN2B subunit, bind at a dimer interface between GluN1 and GluN2B subunit N‐terminal domains (NTDs). Polyamines act by shielding negative charges present on GluN1 and GluN2B NTD lower lobes, allowing their close apposition, an effect that in turn prevents NTD clamshell closure. Our work reveals the mechanistic basis for positive allosteric modulation of NMDARs. It provides the first example of an intersubunit binding site in this class of receptors, a discovery that holds promise for future drug interventions.