Amino-terminal ligands prolong NMDA Receptor-mediated EPSCs.
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.
Vollum Institute, Oregon Health and Science University, Portland, Oregon 97239, USA. tovark@ohsu.edu
Kenneth R
KR
Tovar
Gary L
GL
Westbrook
D000465:Algorithms; D000818:Animals; D001369:Axons / Q000502:physiology; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D055724:Electrophysiological Phenomena; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects* / Q000235:genetics; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D007700:Kinetics; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects; D015032:Zinc / Q000494:pharmacology
D002614:Chelating Agents; D018691:Excitatory Amino Acid Antagonists; D008024:Ligands; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D015032:Zinc; C010739:ifenprodil