NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

Chung, ChiHye

doi:10.1007/s10059-013-0113-y

Cited by 22 publications

(15 citation statements)

References 67 publications

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“…It is hypothesized that circulating BCAAs could have an important role in glutamate synthesis and could also buffer toxic levels of glutamate [ 35 ]. Glutamate is the most abundant excitatory neurotransmitter and binds to cell surface receptors like α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and N-methyl-D-aspartate receptors [ 36 ]. Because N-methyl-D-aspartate-receptor hypofunction seems to be related to calcium ion dysregulation and impaired synaptic plasticity [ 37 ], it is possible that the association of reduced levels of BCAA to dementia and AD is mediated through this pathway [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

Association of branched‐chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Tynkkynen

Chouraki

Lee

et al. 2018

Alzheimer's & Dementia

209

210

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Introduction Metabolite, lipid, and lipoprotein lipid profiling can provide novel insights into mechanisms underlying incident dementia and Alzheimer’s disease. Methods We studied eight prospective cohorts with 22,623 participants profiled by nuclear magnetic resonance or mass spectrometry metabolomics. Four cohorts were used for discovery with replication undertaken in the other four to avoid false positives. For metabolites that survived replication, combined association results are presented. Results Over 246,698 person-years, 995 and 745 cases of incident dementia and Alzheimer’s disease were detected, respectively. Three branched-chain amino acids (isoleucine, leucine, and valine), creatinine and two very low density lipoprotein (VLDL)-specific lipoprotein lipid subclasses were associated with lower dementia risk. One high density lipoprotein (HDL; the concentration of cholesterol esters relative to total lipids in large HDL) and one VLDL (total cholesterol to total lipids ratio in very large VLDL) lipoprotein lipid subclass was associated with increased dementia risk. Branched-chain amino acids were also associated with decreased Alzheimer’s disease risk and the concentration of cholesterol esters relative to total lipids in large HDL with increased Alzheimer’s disease risk. Discussion Further studies can clarify whether these molecules play a causal role in dementia pathogenesis or are merely markers of early pathology.

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Section: Discussionmentioning

confidence: 99%

Association of branched‐chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Tynkkynen

Chouraki

Lee

et al. 2018

Alzheimer's & Dementia

209

210

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“…These parameters of ion conductance are largely regulated by amino acid signaling motifs in the aminoterminal domain (NTD) and transmembrane domains (TMDs). However, NMDARs also operate in calcium-independent ways to regulate neuronal plasticity (Birnbaum, Bali, Rajendran, Nitsch, & Tackenberg, 2015; Chung, 2013; Nabavi et al, 2013; Vissel, Krupp, Heinemann & Westbrook, 2001; Li et al, 2016; Stein, Gray, & Zito, 2015; Dore et al, 2017). Glutamate binding to NMDARs can produce signals in the postsynaptic neuron in the absence of calcium conductance, via direct protein-protein interactions mediated by the carboxy-terminal domain (CTD) of the GluN2 subunits (Sanz-Clemente, Nicoll, & Roche, 2013; Blanke & VanDongen, 2009; Maki, Aman, Amico-Ruvio, Kussius & Popescru, 2012; Dore & Malinow, 2015; Dore, Aow, & Malinow, 2016; Aow, Dore & Malinow, 2015).…”

Section: Introductionmentioning

confidence: 99%

Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons

et al. 2019

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N-methyl-D-aspartate receptors (NMDARs) are glutamatergic receptors that take part in excitatory synaptic transmission and drive functional and structural neuronal plasticity, including activity-dependent changes in dendritic morphology. Forebrain NMDARs contribute to neuronal plasticity in at least two ways: through calcium-mediated processes or via direct intracellular postsynaptic signaling. Both properties are regulated by the GluN2 subunits. However, the separate contributions of these properties to the regulation of dendritic morphology are unknown. We created transgenic mice that express chimeric GluN2 subunits and examined the impact on pyramidal cell dendritic morphology in hippocampal region CA1. Golgi-Cox impregnation and transgenic expression of green fluorescent protein were employed to visualize dendritic arbors. In adult mice with a predominantly native GluN2A background, overexpression of the GluN2B carboxy terminus increased the total path of the dendritic arbor without affecting branch number or tortuosity. Overexpressing the amino terminus and transmembrane domains of GluN2B had little effect. It may be inferred from these results that NMDAR-dependent intracellular signaling regulates dendritic morphology of hippocampal pyramidal cells more so than calcium conductance dynamics. The findings add to the understanding of NMDAR-mediated signaling in hippocampal neurons and support re-investigation of the molecular underpinnings of NMDAR involvement in postnatal dendrite maturation.

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“…It has been thought for a long time that the levels of Ca 2+ influx through NMDARs determine the induction of either LTP (high Ca 2+ influx or LTD (mild Ca 2+ influx). 12 Nevertheless, a recent study showed that Ca 2+ flux is not essential for the induction of NMDAR-LTD, whereas glutamate binding to the receptor is required. 13 NMDAR signaling independently of ion flux has already been proposed to regulate NMDAR phosphorylation and endocytosis.…”

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confidence: 99%

Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss

et al. 2015

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Synaptic loss is one of the major features of Alzheimer's disease (AD) and correlates with the degree of dementia. N-methyl-d-aspartate receptors (NMDARs) have been shown to mediate downstream effects of the β-amyloid peptide (Aβ) in AD models. NMDARs can trigger intracellular cascades via Ca2+ entry, however, also Ca2+-independent (metabotropic) functions of NMDARs have been described. We aimed to determine whether ionotropic or metabotropic NMDAR signaling is required for the induction of synaptic loss by Aβ. We show that endogenous Aβ as well as exogenously added synthetic Aβ oligomers induced dendritic spine loss and reductions in pre- and postsynaptic protein levels in hippocampal slice cultures. Synaptic alterations were mitigated by blocking glutamate binding to NMDARs using NMDAR antagonist APV, but not by preventing ion flux with Ca2+ chelator BAPTA or open-channel blockers MK-801 or memantine. Aβ increased the activity of p38 MAPK, a kinase involved in long-term depression and inhibition of p38 MAPK abolished the loss of dendritic spines. Aβ-induced increase of p38 MAPK activity was prevented by APV but not by BAPTA, MK-801 or memantine treatment highlighting the role of glutamate binding to NMDARs but not Ca2+ flux for synaptic degeneration by Aβ. We further show that treatment with the G protein inhibitor pertussis toxin (PTX) did not prevent dendritic spine loss in the presence of Aβ oligomers. Our data suggest that Aβ induces the activation of p38 MAPK and subsequent synaptic loss through Ca2+ flux- and G protein-independent mechanisms.

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NMDA Receptor as a Newly Identified Member of the Metabotropic Glutamate Receptor Family: Clinical Implications for Neurodegenerative Diseases

Cited by 22 publications

References 67 publications

Association of branched‐chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Association of branched‐chain amino acids and other circulating metabolites with risk of incident dementia and Alzheimer's disease: A prospective study in eight cohorts

Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons

Calcium flux-independent NMDA receptor activity is required for Aβ oligomer-induced synaptic loss

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