A structurally derived model of subunit‐dependent NMDA receptor function

摘要

Key points class="unordered" style="list-style-type:disc" id="tjp13103-list-0001">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.