About this item:

101 Views | 3 Downloads

Author Notes:

Corresponding author A. J. Gibb: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.gibb@ucl.ac.uk

K.K.O., M.J.M. and K.M.V. conducted experiments at Emory University.

K.K.O. implemented the missed event fitting in MATLAB. S.A.K., P.B. and C.B. performed molecular dynamics simulations and analyses.

D.C.L. contributed to interpretation of molecular dynamics data.

K.K.O., M.J.M., S.F.T., S.A.K. and A.J.G. performed data analysis.

A.J.G. and S.F.T. performed simulations.

All authors contributed to writing the manuscript.

All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work.

All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

We thank Phoung Le and Jing Zhang for outstanding technical assistance.

We thank Chris Shelley for critical comments on the manuscript.

S.F.T. is a co‐founder of NeurOp Inc., a PI on a research grant from Janssen to Emory University, and a member of the Scientific Advisory Board for Sage Therapeutics.

Subjects:

Research Funding:

This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS, NIH) (NS036654, NS065371; S.F.T.), the Wellcome Trust (A.J.G.) and the BBSRC (A.J.G.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Neurosciences
  • Physiology
  • Neurosciences & Neurology
  • NMDA receptor
  • Synaptic mechanisms modelling
  • Activation kinetics
  • D-ASPARTATE RECEPTORS
  • LIGAND-BINDING DOMAIN
  • POSITIVE ALLOSTERIC MODULATORS
  • IONOTROPIC GLUTAMATE RECEPTORS
  • COMPACTA DOPAMINERGIC-NEURONS
  • CULTURED HIPPOCAMPAL-NEURONS
  • AGGREGATED MARKOV-PROCESSES
  • MEDIATED SYNAPTIC CURRENTS
  • MAJOR DEPRESSIVE DISORDER
  • CENTRAL-NERVOUS-SYSTEM

A structurally derived model of subunit-dependent NMDA receptor function

Tools:

Journal Title:

Journal of Physiology

Volume:

Volume 596, Number 17

Publisher:

, Pages 4057-4089

Type of Work:

Article | Final Publisher PDF

Abstract:

Key points: The kinetics of NMDA receptor (NMDAR) signalling are a critical aspect of the physiology of excitatory synaptic transmission in the brain. Here we develop a mechanistic description of NMDAR function based on the receptor tetrameric structure and the principle that each agonist-bound subunit must undergo some rate-limiting conformational change after agonist binding, prior to channel opening. By fitting this mechanism to single channel data using a new MATLAB-based software implementation of maximum likelihood fitting with correction for limited time resolution, rate constants were derived for this mechanism that reflect distinct structural changes and predict the properties of macroscopic and synaptic NMDAR currents. The principles applied here to develop a mechanistic description of the heterotetrameric NMDAR, and the software used in this analysis, can be equally applied to other heterotetrameric glutamate receptors, providing a unifying mechanistic framework to understanding the physiology of glutamate receptor signalling in the brain. Abstract: NMDA receptors (NMDARs) are tetrameric complexes comprising two glycine-binding GluN1 and two glutamate-binding GluN2 subunits. Four GluN2 subunits encoded by different genes can produce up to 10 different di- and triheteromeric receptors. In addition, some neurological patients contain a de novo mutation or inherited rare variant in only one subunit. There is currently no mechanistic framework to describe tetrameric receptor function that can be extended to receptors with two different GluN1 or GluN2 subunits. Here we use the structural features of glutamate receptors to develop a mechanism describing both single channel and macroscopic NMDAR currents. We propose that each agonist-bound subunit undergoes some rate-limiting conformational change after agonist binding, prior to channel opening. We hypothesize that this conformational change occurs within a triad of interactions between a short helix preceding the M1 transmembrane helix, the highly conserved M3 motif encoded by the residues SYTANLAAF, and the linker preceding the M4 transmembrane helix of the adjacent subunit. Molecular dynamics simulations suggest that pre-M1 helix motion is uncorrelated between subunits, which we interpret to suggest independent subunit-specific conformational changes may influence these pre-gating steps. According to this interpretation, these conformational changes are the main determinants of the key kinetic properties of NMDA receptor activation following agonist binding, and so these steps sculpt their physiological role. We show that this structurally derived tetrameric model describes both single channel and macroscopic data, giving a new approach to interpreting functional properties of synaptic NMDARs that provides a logical framework to understanding receptors with non-identical subunits.

Copyright information:

© 2018 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
Export to EndNote