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

作者：Fedele Laura; Newcombe Joseph; Topf Maya^*; Gibb Alasdair; Harvey Robert J^*; Smart Trevor G^*

来源：Nature Communications, 2018, 9(1): 957.

DOI：10.1038/s41467-018-02927-4

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 disorders. Of note, the NMDAR channel mutant GluN2BV618G unusually allowed Mg2+ permeation, whereas nearby N615I reduced Ca2+ permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations.

• 出版日期2018-3-6