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1 Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, GA 30322-3090, USA
Fast desensitization is an important regulatory mechanism of neuronal NMDA receptor function. Previous work suggests that fast desensitization of NR1/NR2A receptors is caused by ambient zinc, and that a positive allosteric interaction occurs between the extracellular zinc-binding amino terminal domain and the glutamate-binding domain of NR2A. The relaxation of macroscopic currents in the presence of zinc reflects a shift to a new equilibrium due to increased zinc affinity following the binding of glutamate. Here we demonstrate that this allosteric coupling reflects interactions within the NR2A subunit, and that the affinity of zinc for its binding site is regulated by glutamate binding and not by glycine binding nor by channel pore opening. We fit an explicit model to experimental data over a wide range of parameters, demonstrating that allosteric theory can quantitatively account for the fast zinc-dependent component of desensitization for NR1/NR2A NMDA receptors. We subsequently use this model to evaluate the effects of extracellular zinc on NR1/NR2A excitatory postsynaptic currents (EPSCs) by simulating the response to a brief synaptic-like pulse of glutamate. Modelling results show that zinc at a steady-state concentration of at least 100 nM has a significant effect on the amplitude of NMDA EPSCs but that concurrent release of 10 µM zinc with synaptic glutamate release has little effect on the amplitude of a single NR1/NR2A NMDA EPSC. These data suggest that while steady-state zinc can regulate the amplitude of synaptic NMDA currents, zinc co-released with glutamate will only have significant impact under conditions of high frequency activity or at concentrations high enough to cause voltage-dependent channel block.
(Received 1 August 2005;
accepted after revision 13 September 2005;
first published online 15 September 2005)
Corresponding author K. Erreger: 7124 MRBIII, 465 21st Ave S., Department of Molecular Physiology & Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Email: kevin.erreger{at}vanderbilt.edu
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