New Insights into the Not-So-New NR3 Subunits of <i>N</i>-Methyl-d-aspartate Receptor: Localization, Structure, and Function

Low, Chian-Ming; Wee, Karen Siaw-Ling

doi:10.1124/mol.110.064006

Cited by 87 publications

(65 citation statements)

References 95 publications

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“…In the hippocampus and cortex, glutamate released from pyramidal neurons binds to two types of glutamate receptors with channel-gating properties: the a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate subtypes and the N-methyl-d-aspartate (NMDA) subtypes. At the molecular level, NMDA receptors (NMDARs) are transmembrane channel-forming heteromers assembled by the obligatory NR1 subunit (GluN1) and modulatory NR2/3 subunits (GluN2A, 2B, 2C and 2D for Glu binding; GluN3A and GluN3B for Gly binding) (Low and Wee, 2010; Nong et al, 2003; Stephenson, 2001). Upon glutamate binding, activated NMDA receptors permit Ca 2+ influx and an instant rise in postsynaptic Ca 2+ levels; higher levels induce LTP while moderate levels induce LTD (Kennedy and Ehlers, 2006).…”

Section: Synapses and Cognitive Functionmentioning

confidence: 99%

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

Yan

Fan

Zhou

et al. 2016

Neuroscience & Biobehavioral Reviews

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Over the past two decades, many studies have identified significant contributions of toxic β-amyloid peptides (Aβ) to the etiology of Alzheimer’s disease (AD), which is the most common age-dependent neurodegenerative disease. AD is also recognized as a disease of synaptic failure. Aβ, generated by sequential proteolytic cleavages of amyloid precursor protein (APP) by BACE1 and γ-secretase, is one of major culprits that cause this failure. In this review, we summarize current findings on how BACE1-cleaved APP products impact learning and memory through proteins localized on glutamatergic, GABAergic, and dopaminergic synapses. Considering the broad effects of Aβ on all three types of synapses, BACE1 inhibition emerges as a practical approach for ameliorating Aβ-mediated synaptic dysfunctions. Since BACE1 inhibitory drugs are currently in clinical trials, this review also discusses potential complications arising from BACE1 inhibition. We emphasize that the benefits of BACE1 inhibitory drugs will outweigh the concerns.

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Section: Synapses and Cognitive Functionmentioning

confidence: 99%

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

Yan

Fan

Zhou

et al. 2016

Neuroscience & Biobehavioral Reviews

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“…1 and 2). These subunits are known as "inhibitory subunits" in the brain as they are glutamate-insensitive but excited by glycine only (35). Currents induced by glycine in NR1/NR3 diheteromers are insensitive to MK-801 or memantine (58).…”

Section: Nmdar-induced Whole Cell Currents In Rbcsmentioning

confidence: 99%

N-methyl-d-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation

Makhro

Hänggi

Goede

et al. 2013

American Journal of Physiology-Cell Physiology

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The presence of N-methyl-D-aspartate receptor (NMDAR) was previously shown in rat red blood cells (RBCs) and in a UT-7/Epo human myeloid cell line differentiating into erythroid lineage. Here we have characterized the subunit composition of the NMDAR and monitored its function during human erythropoiesis and in circulating RBCs. Expression of the NMDARs subunits was assessed in erythroid progenitors during ex vivo erythropoiesis and in circulating human RBCs using quantitative PCR and flow cytometry. Receptor activity was monitored using a radiolabeled antagonist binding assay, live imaging of Ca 2ϩ uptake, patch clamp, and monitoring of cell volume changes. The receptor tetramers in erythroid precursor cells are composed of the NR1, NR2A, 2C, 2D, NR3A, and 3B subunits of which the glycine-binding NR3A and 3B and glutamate-binding NR2C and 2D subunits prevailed. Functional receptor is required for survival of erythroid precursors. Circulating RBCs retain a low number of the receptor copies that is higher in young cells compared with mature and senescent RBC populations. In circulating RBCs the receptor activity is controlled by plasma glutamate and glycine. Modulation of the NMDAR activity in RBCs by agonists or antagonists is associated with the alterations in whole cell ion currents. Activation of the receptor results in the transient Ca 2ϩ accumulation, cell shrinkage, and alteration in the intracellular pH, which is associated with the change in hemoglobin oxygen affinity. Thus functional NMDARs are present in erythroid precursor cells and in circulating RBCs. These receptors contribute to intracellular Ca 2ϩ homeostasis and modulate oxygen delivery to peripheral tissues.

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“…The NMDAR is composed of several subunits, namely the glycine-binding core NR1, the glutamate-binding NR2, including NR2A-D, and the recently discovered glycinebinding NR3, which includes NR3A and NR3B (35,48,56,144). The presence of NR1 is required for forming functional NMDARs, and this subunit combines with several NR2 and/ or NR3 subunits to form heteromeric receptors (2,40,218).…”

Section: Nmdar and Its Antagonistsmentioning

confidence: 99%

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

Wang

Pinto-Duarte

Sejnowski

et al. 2013

Antioxidants & Redox Signaling

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Significance: Schizophrenia is a complex neuropsychiatric disorder affecting around 1% of the population worldwide. Its mode of inheritance suggests a multigenic neurodevelopmental disorder with symptoms appearing during late adolescence/early adulthood, with its onset strongly influenced by environmental stimuli. Many neurotransmitter systems, including dopamine, glutamate, and gamma-aminobutyric acid, show alterations in affected individuals, and the behavioral and physiological characteristics of the disease can be mimicked by drugs that produce blockade of N-methyl-d-aspartate glutamate receptors (NMDARs). Recent Advances: Mounting evidence suggests that drugs that block NMDARs specifically impair the inhibitory capacity of parvalbumin-expressing (PV+) fast-spiking neurons in adult and developing rodents, and alterations in these inhibitory neurons is one of the most consistent findings in the schizophrenic postmortem brain. Disruption of the inhibitory capacity of PV+ inhibitory neurons will alter the functional balance between excitation and inhibition in prefrontal cortical circuits producing impairment of working memory processes such as those observed in schizophrenia. Critical Issues: Mechanistically, the effect of NMDAR antagonists can be attributed to the activation of the Nox2-dependent reduced form of nicotinamide adenine dinucleotide phosphate oxidase pathway in cortical neurons, which is consistent with the emerging role of oxidative stress in the pathogenesis of mental disorders, specifically schizophrenia. Here we review the mechanisms by which NMDAR antagonists produce lasting impairment of the cortical PV+ neuronal system and the roles played by Nox2-dependent oxidative stress mechanisms. Future Directions: The discovery of the pathways by which oxidative stress leads to unbalanced excitation and inhibition in cortical neural circuits opens a new perspective toward understanding the biological underpinnings of schizophrenia.

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New Insights into the Not-So-New NR3 Subunits of N-Methyl-d-aspartate Receptor: Localization, Structure, and Function

Cited by 87 publications

References 95 publications

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

N-methyl-d-aspartate receptors in human erythroid precursor cells and in circulating red blood cells contribute to the intracellular calcium regulation

How Nox2-Containing NADPH Oxidase Affects Cortical Circuits in the NMDA Receptor Antagonist Model of Schizophrenia

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