Unbound MEDLINE

Amino-terminal ligands prolong NMDA Receptor-mediated EPSCs.

Abstract

The amino-terminal domains of NMDA receptor subunits are important for receptor assembly and desensitization, and incorporate the high-affinity binding sites for zinc and ifenprodil. These amino-terminal ligands are thought of as subunit-specific receptor inhibitors. However, multiple NMDA receptor subtypes contribute to EPSCs at wild-type hippocampal synapses. To understand the action of amino-terminal ligands, we first used cultured hippocampal neurons from N2A and N2B knock-out mice. EPSCs from these neurons have properties that are consistent with N1/N2B and N1/N2A diheteromeric receptors, respectively. As expected, zinc reduced the EPSC peak amplitude from N2B KO neurons, but surprisingly also prolonged the deactivation, resulting in a marked redistribution of charge. Consistent with prolongation of the EPSC, zinc produced a longer latency to first opening of glutamate-bound receptors, which resulted in a decrease in the number of receptors that opened by the peak. Ifenprodil had similar effects on EPSCs from N2A KO neurons. In neurons from wild-type mice, zinc or ifenprodil reduced the EPSC peak, but only zinc caused significant charge redistribution, consistent with a small contribution of N1/N2B diheteromers in these neurons. Our results indicate that ligand binding to amino-terminal domains can alter the behavior of synaptic NMDA receptors under the nonequilibrium conditions of glutamate release during synaptic transmission. By prolonging EPSCs, amino-terminal ligands could markedly affect the computational properties of NMDA receptors and could potentially be exploited for therapeutic purposes.

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  • Authors

    Tovar KR, Westbrook GL

    Source

    The Journal of neuroscience : the official journal of the Society for Neuroscience 32:23 2012 Jun 6 pg 8065-73

    MeSH

    Algorithms
    Animals
    Axons
    Cells, Cultured
    Chelating Agents
    Dose-Response Relationship, Drug
    Electrophysiological Phenomena
    Excitatory Amino Acid Antagonists
    Excitatory Postsynaptic Potentials
    Hippocampus
    Kinetics
    Ligands
    Mice
    Mice, Knockout
    Patch-Clamp Techniques
    Piperidines
    Receptors, N-Methyl-D-Aspartate
    Synaptic Transmission
    Zinc

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    22674281