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A structurally derived model of subunit-dependent NMDA receptor function.

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.

SUBMITTER: Gibb AJ

PROVIDER: S-EPMC6117563 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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A structurally derived model of subunit-dependent NMDA receptor function.

Gibb Alasdair J AJ Ogden Kevin K KK McDaniel Miranda J MJ Vance Katie M KM Kell Steven A SA Butch Chris C Burger Pieter P Liotta Dennis C DC Traynelis Stephen F SF

The Journal of physiology 20180801 17

<h4>Key points</h4>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 imp ...[more]

PMID: 29917241

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Project description:BackgroundPostherpetic neuralgia is spontaneous pain and allodynia that persist long after the disappearance of the cutaneous lesions caused by herpes zoster. Inoculation of mice with herpes simplex virus-1 causes herpes zoster-like skin lesions and herpetic and postherpetic pain. Although NMDA receptors have been suggested to be involved in postherpetic pain as in other types of neuropathic pain, the neural mechanism remains unclear. NMDA receptor NR2B subunit is the most tyrosine-phosphorylated protein in the brain, and Tyr1472 is the major phosphorylation site of this subunit.ResultsTo elucidate the role of Tyr1472 phosphorylation of the NR2B subunit in herpetic and postherpetic allodynia, we inoculated herpes simplex virus-1 into the unilateral hind paw of knock-in mice with a mutation of Tyr1472 of the NR2B subunit to Phe (Y1472F-KI). On day 7 post-inoculation, acute herpetic allodynia was observed in more than 80% of the inoculated wild-type and Y1472F-KI mice. Y1472F-KI mice showed significantly reduced intensity and incidence of postherpetic allodynia on days 45-50 post-inoculation as compared with wild-type mice. The innervation in the skin at the postherpetic neuralgia phase was retained to a greater extent in the Y1472F-KI mice. The level of activating transcription factor-3 mRNA, a marker of axonal damage, increased much less in the dorsal root ganglia (DRGs) of Y1472F-KI mice than in those of wild-type mice; and the level of nerve growth factor mRNA significantly increased in wild-type mice, but not at all in Y1472F-KI mice on day 7 post-inoculation. Production of nerve growth factor was at the basal level in the skin of both groups of mice on day 50 post-inoculation. Nerve growth factor and glial cell-derived neurotrophic factor stimulated neurite outgrowth of cultured DRG neurons from Y1472F-KI mice, similarly or less so as they did the outgrowth of those from wild-type mice. Wild-type DRG neurons were more susceptible to glutamate neurotoxicity than Y1472F-KI ones.ConclusionsTaken together, the present data suggest that phosphorylation of the NR2B subunit at its Tyr1472 is involved in the development of postherpetic allodynia due to nerve damage and that the nerve damage at the acute herpetic phase is correlated with the incidence of postherpetic pain.

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A structurally derived model of subunit-dependent NMDA receptor function.

Publications

A structurally derived model of subunit-dependent NMDA receptor function.

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