Abstract
A variety of de novo and inherited missense mutations associated with neurological disorders are found in the NMDA receptor M4 transmembrane helices, which are peripheral to the pore domain in eukaryotic ionotropic glutamate receptors. Subsets of these mutations affect receptor gating with dramatic effects, including in one instance halting it, occurring at a conserved glycine near the extracellular end of M4. Functional experiments and molecular dynamic simulations of constructs with and without substitutions at this glycine indicate that it acts as a hinge, permitting the intracellular portion of the ion channel to laterally expand. This expansion stabilizes long-lived open states leading to slow deactivation and high Ca2+ permeability. Our studies provide a functional and structural framework for the effect of missense mutations on NMDARs at central synapses and highlight how the M4 segment may represent a pathway for intracellular modulation of NMDA receptor function.
Highlights
A variety of de novo and inherited missense mutations associated with neurological disorders are found in the NMDA receptor M4 transmembrane helices, which are peripheral to the pore domain in eukaryotic ionotropic glutamate receptors
Ionotropic glutamate receptors, including AMPA (AMPAR) and NMDA (NMDAR) receptor subtypes, are glutamate-gated ion channels found throughout the brain and participate in almost all brain functions
Numerous de novo and inherited missense mutations have been identified in Ionotropic glutamate receptors (iGluRs) subunits that are associated with a wide spectrum of disorders, including epilepsy, intellectual disability, movement disorders, and schizophrenia[4,5,6,7]
Summary
A variety of de novo and inherited missense mutations associated with neurological disorders are found in the NMDA receptor M4 transmembrane helices, which are peripheral to the pore domain in eukaryotic ionotropic glutamate receptors. Subsets of these mutations affect receptor gating with dramatic effects, including in one instance halting it, occurring at a conserved glycine near the extracellular end of M4. We address the contribution of these M4 missense mutations to receptor function Many of these mutations impact receptor gating, the most notable and robust effects occur at a highly conserved glycine (Supplementary Figure 1) positioned near the extracellular end of the M4 segments. Missense mutations at this position in the GluN1 and GluN2B subunits have been identified in multiple patients, and the resulting changes in side chain properties can be either great
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