Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

ABSTRACT: Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg²⁺ block. In addition, we provide new views on Mg²⁺ and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological di

SUBMITTER: Fedele L 

PROVIDER: S-EPMC5840332 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature