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

Fedele, L. and Newcombe, J. and Topf, Maya and Gibb, A. and Harvey, R.J. and Smart, T.G. (2018) Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties. Nature Communications 9 (1), p. 957. ISSN 2041-1723.

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 Mg block. In addition, we provide new views on Mg 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 GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca 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.

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