期刊
NEUROPHARMACOLOGY
卷 109, 期 -, 页码 196-204出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuropharm.2016.06.008
关键词
Glutamate receptor; NMDA receptor; Zinc; Mutation; Synapse; Epilepsy
资金
- Fondation pour la Recherche Medicale ('Equipe FRM' grant) [DEQ2000326520]
- French government ('Investissements d'Avenir' MEMO LIFE) [ANR-10-LABX-54]
- French government (PSL* Research University) [ANR-11-IDEX-0001-02]
- University Pierre-et-Marie-Curie (UPMC Paris 6)
Recent human genetic studies have identified a surprisingly high number of alterations in genes encoding NMDA receptor (NMDAR) subunits in several common brain diseases. Among NMDAR subunits, the widely-expressed GIuN2A subunit appears particularly affected, with tens of de novo or inherited mutations associated with neurodevelopmental conditions including childhood epilepsies and cognitive deficits. Despite the increasing identification of NMDAR mutations of clinical interest, there is still little information about the effects of the mutations on receptor and network function. Here we analyze the impact on receptor expression and function of nine GIuN2A missense (i.e. single-point) mutations targeting the N-terminal domain, a large regulatory region involved in subunit assembly and allosteric signaling. While several mutations produced no or little apparent effect on receptor expression, gating and pharmacology, two showed a drastic expression phenotype and two resulted in marked alterations in the sensitivity to zinc, a potent allosteric inhibitor of GluN1/GluN2A receptors and modulator of excitatory synaptic transmission. Surprisingly, both increase (GluN2A-R370W) and decrease (GluN2A-P79R) of zinc sensitivity were observed on receptors containing either one or two copies of the mutated subunits. Overexpression of the mutant subunits in cultured rat neurons confirmed the results from heterologous expression. These results, together with previously published data, indicate that disease causing mutations in NMDARs produce a wide spectrum of receptor alterations, at least in vitro. They also point to a critical role of the zinc-NMDAR interaction in neuronal function and human health. (C) 2016 Elsevier Ltd. All rights reserved.
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