title: Molecular basis of positive allosteric modulation of GluN2B NMDA receptors by polyamines.
abstract: 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.
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS UMR 8197, INSERM U1024, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Mony
authors.forename: Shujia
authors.initials: S
authors.lastname: Zhu
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Carvalho
authors.forename: Pierre
authors.initials: P
authors.lastname: Paoletti
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D000818:Animals; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011073:Polyamines / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D021122:Protein Subunits / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D016415:Sequence Alignment
chemical_list: D011073:Polyamines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate