title: Postsynaptic density protein-95 regulates NMDA channel gating and surface expression.
abstract: NMDA receptors (NMDARs) colocalize with postsynaptic density protein-95 (PSD-95), a multivalent synaptic scaffolding protein and core component of the postsynaptic density, at excitatory synapses. Although much is known about the identity and properties of scaffolding proteins, little is known about their actions on NMDAR function. Here we show that association of PSD-95 with NMDARs modulates channel gating and surface expression. PSD-95 increases the number of functional channels at the cell surface and channel opening rate of NMDARs, with little or no change in conductance, reversal potential, or mean open time. We show further that PSD-95 increases NMDAR surface expression by increasing the rate of channel insertion and decreasing the rate of channel internalization. The PDZ (PSD-95, discs large, zona occludens-1) binding motif at the distal end of the NR2 C-terminal tail is critical to the actions of PSD-95 on NMDAR function and surface expression. Given that activity bi-directionally modifies synaptic levels of PSD-95, our findings suggest a novel mechanism for activity-dependent regulation of NMDARs at central synapses.
authors.affiliation: Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461-1975, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: V Arvydas
authors.initials: VA
authors.lastname: Skeberdis
authors.forename: Anna
authors.initials: A
authors.lastname: Francesconi
authors.forename: Michael V L
authors.initials: MV
authors.lastname: Bennett
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D000076122:Disks Large Homolog 4 Protein; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015640:Ion Channel Gating / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D016297:Mutagenesis, Site-Directed; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009865:Oocytes; D025941:Protein Interaction Mapping; D021381:Protein Transport; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D015854:Up-Regulation; D014982:Xenopus laevis
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; C033652:postsynaptic density proteins; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D051528:Guanylate Kinases; D002118:Calcium