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.

Links

Publisher Full Text

Authors

Tovar KR, Westbrook GL

Institution

Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA. tovark@ohsu.edu

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