Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations. (October 2016)

• Record Type: Journal Article
• Authors: Serraz, Benjamin; Grand, Teddy; Paoletti, Pierre
• Is Part Of: Neuropharmacology. Volume 109(2016)
• Page Start: 196
• Page End: 204
• Publication Date: 2016-10
• Subjects: Glutamate receptor -- NMDA receptor -- Zinc -- Mutation -- Synapse -- Epilepsy; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.06.008
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: 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 GluN2A 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 GluN2A 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. Highlights: Mutations in NMDAR subunits have recently been associated to human brain disorders. Eleven missense mutations targeting the GluN2A N-terminal domain were studied. None of the mutations affect the receptor's basic gating properties. Distinct alterations in receptor expression and zinc sensitivity were observed. These results point to an important role of synaptic zinc in human health.