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Reaction mechanism determines NMDA receptor response to repetitive stimulation

Abstract

At central excitatory synapses, N-methyl-d-aspartate (NMDA) receptors, which have a high affinity for glutamate1, produce a slowly rising synaptic current in response to a single transmitter pulse and an additional current after a second, closely timed stimulus2. Here we show, by examining the kinetics of transmitter binding and channel gating in single-channel currents from recombinant NR1/NR2A receptors, that the synaptic response to trains of impulses is determined by the molecular reaction mechanism of the receptor. The rate constants estimated for the activation reaction predict that, after binding neurotransmitter, receptors hesitate for 4 ms in a closed high-affinity conformation before they either proceed towards opening or release neurotransmitter, with about equal probabilities. Because only about half of the initially fully occupied receptors become active, repetitive stimulation elicits currents with distinct waveforms depending on pulse frequency. This high-affinity/low-efficiency activation mechanism might serve as a link between stimulation frequency and the directionality of the ensuing synaptic plasticity.

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Figure 1: Single-channel NR activity at 5 µM glutamate.
Figure 2: NR activity at several glutamate concentrations.
Figure 3: Simulated NR macroscopic responses to a single glutamate pulse.
Figure 4: NR response to repetitive stimulation (1-ms pulses of 1 mM glutamate).

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Acknowledgements

We thank T. Bailey, M. Teeling and C. Nicolai for technical assistance. This work was supported by NIH grants to G.P. and A.A.

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Correspondence to Gabriela Popescu.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

This figure illustrates the kinetic schemes used to fit single channel data obtained from NR1/2A receptors. (PPT 42 kb)

Supplementary Table S1

This document contains a table summarizing time constants for closed and open components in single channel currents NR1/2A receptors. (DOC 32 kb)

Supplementary Table S2

This file contains a table summarizing rate constants for L-mode gating NR1/2A receptors optimized with each of the kinetic schemes illustrated in Supplementary Figure S1. (DOC 44 kb)

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Popescu, G., Robert, A., Howe, J. et al. Reaction mechanism determines NMDA receptor response to repetitive stimulation. Nature 430, 790–793 (2004). https://doi.org/10.1038/nature02775

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