title: Kinetic contributions to gating by interactions unique to N-methyl-D-aspartate (NMDA) receptors.
abstract: Among glutamate-gated channels, NMDA receptors produce currents that subside with unusually slow kinetics, and this feature is essential to the physiology of central excitatory synapses. Relative to the homologous AMPA and kainate receptors, NMDA receptors have additional intersubunit contacts in the ligand binding domain that occur at both conserved and non-conserved sites. We examined GluN1/GluN2A single-channel currents with kinetic analyses and modeling to probe these class-specific intersubunit interactions for their role in glutamate binding and receptor gating. We found that substitutions that eliminate such interactions at non-conserved sites reduced stationary gating, accelerated deactivation, and imparted sensitivity to aniracetam, an AMPA receptor-selective positive modulator. Abolishing unique contacts at conserved sites also reduced stationary gating and accelerated deactivation. These results show that contacts specific to NMDA receptors, which brace the heterodimer interface within the ligand binding domain, stabilize actively gating receptor conformations and result in longer bursts and slower deactivations. They support the view that the strength of the heterodimer interface modulates gating in both NMDA and non-NMDA receptors and that unique interactions at this interface are responsible in part for basic differences between the kinetics of NMDA and non-NMDA currents at glutamatergic synapses.
authors.affiliation: From the Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, New York 14214.
authors.forename: William F
authors.initials: WF
authors.lastname: Borschel
authors.affiliation: From the Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, New York 14214.
authors.forename: Kirstie A
authors.initials: KA
authors.lastname: Cummings
authors.affiliation: From the Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, New York 14214.
authors.forename: LeeAnn K
authors.initials: LK
authors.lastname: Tindell
authors.affiliation: From the Department of Biochemistry, University at Buffalo, State University of New York, Buffalo, New York 14214 popescu@buffalo.edu.
authors.forename: Gabriela K
authors.identifier: http://orcid.org/0000-0003-4658-2002
authors.initials: GK
authors.lastname: Popescu
mesh_terms: D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D018360:Crystallography, X-Ray; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D015640:Ion Channel Gating; D008024:Ligands; D008564:Membrane Potentials / Q000502:physiology*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018697:Nootropic Agents / Q000737:chemistry* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011760:Pyrrolidinones / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D018697:Nootropic Agents; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; C036466:aniracetam
keywords: N-methyl-d-aspartate receptor (NMDA receptor, NMDAR); activation mechanism; gating; ionotropic glutamate receptor; kinetics; receptor structure-function; synaptic transmission