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NMDA receptors: linking physiological output to biophysical operation

Nature Reviews Neuroscience volume 18, pages 236–249 (2017)Cite this article

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Key Points

  • NMDA receptor isoforms respond to glutamate with distinct kinetics and have dynamic, complex and incompletely delineated expression profiles; precise mechanistic information for specific receptor isoforms is derived from recombinant preparations.

  • Functional attributes of recombinant receptor current match well to those of the NMDA receptor-mediated response recorded from synaptic and non-synaptic native receptors.

  • Kinetic models derived from one-channel recordings reproduce all known features of the macroscopic response and reveal novel biophysical properties that underlie physiologically salient features of the synaptic current.

  • The NMDA receptor response amplitude and ionic charge transfer, which initiate synaptic plasticity, depend on stimulation frequency as predicted by the kinetic model.

  • The biphasic decay time of the NMDA receptor synaptic response, which sets the window for coincident depolarization, reflects the proportion of receptors gating in distinct kinetic modes. This insight was afforded by statistical evaluation of single-channel behaviour.

  • Assigning molecular structures to the kinetic states postulated by statistically derived models of NMDA receptor activation is an active area of research.

Abstract

NMDA receptors are preeminent neurotransmitter-gated channels in the CNS, which respond to glutamate in a manner that integrates multiple external and internal cues. They belong to the ionotropic glutamate receptor family and fulfil unique and crucial roles in neuronal development and function. These roles depend on characteristic response kinetics, which reflect the operation of the receptors. Here, we review biologically salient features of the NMDA receptor signal and its mechanistic origins. Knowledge of distinctive NMDA receptor biophysical properties, their structural determinants and physiological roles is necessary to understand the physiological and neurotoxic actions of glutamate and to design effective therapeutics.

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Figure 1: Two members of the ionotropic glutamate receptor family have similar structures but distinctive functional output.
Figure 2: Observable features of the NMDA receptor output.
Figure 3: Models of NMDA receptor operation.
Figure 4: Insights from statistical models.

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Acknowledgements

The authors thank members of the Popescu laboratory and the reviewers for insights and helpful suggestions.

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Authors and Affiliations

  1. Department of Biochemistry, University of Buffalo, State University of New York (SUNY), 144 Farber Hall, 3435 Main street, Buffalo, 14214, New York, USA

    Gary J. Iacobucci & Gabriela K. Popescu

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  1. Gary J. Iacobucci
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Correspondence to Gabriela K. Popescu.

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PowerPoint slides

Glossary

Excitatory postsynaptic current

(EPSC).The net flow of positively charged ions into a postsynaptic neuron observed in response to spontaneously occurring or experimentally evoked neurotransmitter release. In the mammalian CNS, this current is the glutamate-gated electrical output of multiple synaptic receptors (synaptic ionotropic glutamate receptors).

Gating reactions

Molecular isomerizations between inactive and active states; specifically, for ion channels, gating refers to the transitions that connect closed (non-conducting) to open (ion-conducting) conformations.

Binding reaction

The physical association between two initially separate entities; it describes the transition from apo (unbound) to liganded receptor states.

Rate constants

Numbers that define the frequency with which transitions occur. They are expressed in s−1 for isomerization reactions.

Reaction mechanism

The pathway of energy changes that are experienced by a molecule during a conformational or chemical transformation; it postulates numerous elementary states in which the system can be found, how these states can interconvert and the rates with which these steps occur.

Open states

Families of kinetic states defined functionally by their ability to pass current; for glutamate receptors, qualifying structures must have the glutamate-binding cleft in a contracted (closed) conformation, which is incompatible with agonist binding or agonist dissociation, and the pore open (conducting).

Desensitized states

Families of conformations defined functionally by their inability to bind to or dissociate from an agonist and their inability to pass current; for glutamate receptors, qualifying structures must have the glutamate-binding cleft in a tight binding-incompatible conformation and the pore closed (non-conducting).

Modes

Distinct patterns of activity that can be discerned in the single-channel record of almost all ion channels; each kinetic pattern or mode reflects a unique reaction mechanism, characterized by different numbers or arrangements of states or/and different values for particular rate constants.

Open probabilities

Parameters used to express quantitatively the activity of ion channels; they express the fraction of time during which the channel is open and allows ionic flow.

Single-channel record

Document that represents a digital sampling of electrical currents produced by the opening of individual channel proteins; it can register the activity of one or several simultaneously active channels.

Simulations

In silico calculations used to predict time-dependent occupancies for kinetic states given a reaction mechanism (model), initial state occupancies and a stimulus defined by duration and amplitude.

Bursts

Sequence of openings and brief closures; for ion channels with the single-channel record containing closures of n distinct durations, n–1 types of bursts can be defined to contain from 1 to n–1 types of closure durations.

Resting states

Families of conformations defined functionally by their ability to recognize and bind to an agonist and their inability to generate an electrical signal; for glutamate receptors, qualifying structures must have the glutamate-binding cleft in an extended binding-compatible conformation and the pore closed (non-conducting).

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Iacobucci, G., Popescu, G. NMDA receptors: linking physiological output to biophysical operation. Nat Rev Neurosci 18, 236–249 (2017). https://doi.org/10.1038/nrn.2017.24

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