Reaction mechanism determines NMDA receptor response to repetitive stimulation

Gabriela Popescu (), Antoine Robert, James R. Howe and Anthony Auerbach
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Gabriela Popescu: University at Buffalo
Antoine Robert: Yale University School of Medicine
James R. Howe: Yale University School of Medicine
Anthony Auerbach: University at Buffalo

Nature, 2004, vol. 430, issue 7001, 790-793

Abstract: 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.

Date: 2004
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DOI: 10.1038/nature02775

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