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https://www.readbyqxmd.com/read/28222314/systematic-variation-of-the-benzenesulfonamide-part-of-the-glun2a-selective-nmda-receptor-antagonist-tcn-201
#1
Sebastian L Müller, Julian A Schreiber, Dirk Schepmann, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
GluN2A subunit containing N-methyl-d-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part...
February 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28185898/sirt2-inhibition-modulate-glutamate-and-serotonin-systems-in-the-prefrontal-cortex-and-induces-antidepressant-like-action
#2
Mercedes Erburu, Irene Muñoz-Cobo, Teresa Diaz-Perdigon, Paolo Mellini, Takayoshi Suzuki, Elena Puerta, Rosa M Tordera
Growing evidence suggests that changes in histone acetylation in specific sites of the chromatin modulate neuronal plasticity and contribute to antidepressant-like action. Sirtuin 2 (SIRT2) is a class III NAD(+)-dependent histone deacetylase involved in transcriptional repression of genes regulating synaptic plasticity. Importantly, a key role for the glutamate system in prefrontal cortex (PFC) synaptic plasticity changes induced by antidepressants has been suggested. Here, we asked whether SIRT2 could be a pharmacological target for depression therapy...
February 6, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28182669/a-de-novo-loss-of-function-grin2a-mutation-associated-with-childhood-focal-epilepsy-and-acquired-epileptic-aphasia
#3
Kai Gao, Anel Tankovic, Yujia Zhang, Hirofumi Kusumoto, Jin Zhang, Wenjuan Chen, Wenshu XiangWei, Gil H Shaulsky, Chun Hu, Stephen F Traynelis, Hongjie Yuan, Yuwu Jiang
OBJECTIVE: N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with various neurological diseases, such as epilepsy and intellectual disability / developmental delay (ID/DD). In this study, we investigated the phenotype and underlying molecular mechanism of a GRIN2A missense mutation identified by next generation sequencing on idiopathic focal epilepsy using in vitro electrophysiology. METHODS: Genomic DNA of patients with epilepsy and ID/DD were sequenced by targeted next-generation sequencing within 300 genes related to epilepsy and ID/DD...
2017: PloS One
https://www.readbyqxmd.com/read/28174519/identifying-the-role-of-glun2a-in-cerebral-ischemia
#4
Yongjun Sun, Long Wang, Zibin Gao
No abstract text is available yet for this article.
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28157099/sex-impact-on-tau-aggregation-and-postsynaptic-protein-levels-in-the-p301l-mouse-model-of-tauopathy
#5
Lucia Buccarello, Giuliano Grignaschi, Anna Maria Castaldo, Alessia Di Giancamillo, Cinzia Domeneghini, Roberto Cosimo Melcangi, Tiziana Borsello
P301L transgenic (tg) mice well mimic features of human tauopathies and provide a good model for investigating the role of tau in neurodegenerative events. We here analyzed the possible interaction among phosphorylation of tau (p-tau), spine injury, neuronal death, and sex in the P301L mouse model of tauopathy. When compared to control mice (ctr), P301L transgenic mice (tg) presented with lower body weight, reduced survival rate, hyperphosphorylated tau, spine injury, and neuronal loss in both cerebral cortex and hippocampus at 15 months of age...
February 1, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28134307/fingolimod-limits-acute-a%C3%AE-neurotoxicity-and-promotes-synaptic-versus-extrasynaptic-nmda-receptor-functionality-in-hippocampal-neurons
#6
Pooja Joshi, Martina Gabrielli, Luisa Ponzoni, Silvia Pelucchi, Matteo Stravalaci, Marten Beeg, Sonia Mazzitelli, Daniela Braida, Mariaelvina Sala, Enrica Boda, Annalisa Buffo, Marco Gobbi, Fabrizio Gardoni, Michela Matteoli, Elena Marcello, Claudia Verderio
Fingolimod, also known as FTY720, is an analogue of the sphingolipid sphingosine, which has been proved to be neuroprotective in rodent models of Alzheimer's disease (AD). Several cellular and molecular targets underlying the neuroprotective effects of FTY720 have been recently identified. However, whether the drug directly protects neurons from toxicity of amyloid-beta (Aβ) still remains poorly defined. Using a combination of biochemical assays, live imaging and electrophysiology we demonstrate that FTY720 induces a rapid increase in GLUN2A-containing neuroprotective NMDARs on the surface of dendritic spines in cultured hippocampal neurons...
January 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28126851/functional-evaluation-of-a-de-novo-grin2a-mutation-identified-in-a-patient-with-profound-global-developmental-delay-and-refractory-epilepsy
#7
Wenjuan Chen, Anel Tankovic, Pieter B Burger, Hirofumi Kusumoto, Stephen F Traynelis, Hongjie Yuan
The N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ionotropic glutamate receptor, plays important roles in normal brain development and a wide range of neurological disorders, including epilepsy. Here, we evaluate for the first time the functional properties of a de novo GRIN2A missense mutation (p.M817V) in the pre-M4 linker in a child with profound global developmental delay and refractory epilepsy. Electrophysiological recordings revealed that the mutant GluN2A(M817V)-containing receptors showed enhanced agonist potency, reduced sensitivity to endogenous negative inhibitors (Mg2+, proton, and zinc), prolonged synaptic-like response time course, increased single channel mean open time, and increased channel open probability...
January 26, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28123030/cocaine-promotes-coincidence-detection-and-lowers-induction-threshold-during-hebbian-associative-synaptic-potentiation-in-prefrontal-cortex
#8
Hongyu Ruan, Wei-Dong Yao
: Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here, we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike-timing-dependent LTP (t-LTP)...
January 25, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28105280/glun2a-selective-pyridopyrimidinone-series-of-nmdar-positive-allosteric-modulators-with-an-improved-in-vivo-profile
#9
Elisia Villemure, Matthew Volgraf, Yu Jiang, Guosheng Wu, Cuong Q Ly, Po-Wai Yuen, Aijun Lu, Xifeng Luo, Mingcui Liu, Shun Zhang, Patrick J Lupardus, Heidi J A Wallweber, Bianca M Liederer, Gauri Deshmukh, Emile Plise, Suzanne Tay, Tzu-Ming Wang, Jesse E Hanson, David H Hackos, Kimberly Scearce-Levie, Jacob B Schwarz, Benjamin D Sellers
The N-methyl-d-aspartate receptor (NMDAR) is an ionotropic glutamate receptor, gated by the endogenous coagonists glutamate and glycine, permeable to Ca(2+) and Na(+). NMDAR dysfunction is associated with numerous neurological and psychiatric disorders, including schizophrenia, depression, and Alzheimer's disease. Recently, we have disclosed GNE-0723 (1), a GluN2A subunit-selective and brain-penetrant positive allosteric modulator (PAM) of NMDARs. This work highlights the discovery of a related pyridopyrimidinone core with distinct structure-activity relationships, despite the structural similarity to GNE-0723...
January 12, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28102473/the-role-of-glun2a-in-cerebral-ischemia-promoting-neuron-death-and-survival-in-the-early-stage-and-thereafter
#10
REVIEW
Yongjun Sun, Xiaokun Cheng, Jie Hu, Zibin Gao
Over-activation of NMDA receptors is a crucial step required for brain damage following a stroke. Although clinical trials for NMDA receptor blockers have failed, the role of GluN2A subunit in cerebral ischemia has been extensively evaluated in recent years. However, the effect of GluN2A on neuron damage induced by cerebral ischemia remains a matter of controversy. The underlying reason may be that GluN2A mediates both pro-death and pro-survival effects. These two effects result from two mutually excluding pathways, Ca(2+) overload-dependent pro-death signaling and C-terminal-dependent pro-survival signaling, respectively...
January 19, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28095420/molecular-mechanism-of-disease-associated-mutations-in-the-pre-m1-helix-of-nmda-receptors-and-potential-rescue-pharmacology
#11
Kevin K Ogden, Wenjuan Chen, Sharon A Swanger, Miranda J McDaniel, Linlin Z Fan, Chun Hu, Anel Tankovic, Hirofumi Kusumoto, Gabrielle J Kosobucki, Anthony J Schulien, Zhuocheng Su, Joseph Pecha, Subhrajit Bhattacharya, Slavé Petrovski, Adam E Cohen, Elias Aizenman, Stephen F Traynelis, Hongjie Yuan
N-methyl-D-aspartate receptors (NMDARs), ligand-gated ionotropic glutamate receptors, play key roles in normal brain development and various neurological disorders. Here we use standing variation data from the human population to assess which protein domains within NMDAR GluN1, GluN2A and GluN2B subunits show the strongest signal for being depleted of missense variants. We find that this includes the GluN2 pre-M1 helix and linker between the agonist-binding domain (ABD) and first transmembrane domain (M1). We then evaluate the functional changes of multiple missense mutations in the NMDAR pre-M1 helix found in children with epilepsy and developmental delay...
January 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28057539/effects-of-ibuprofen-on-cognition-and-nmda-receptor-subunit-expression-across-aging
#12
Alejandra Márquez Loza, Valerie Elias, Carmen P Wong, Emily Ho, Michelle Bermudez, Kathy R Magnusson
Age-related declines in long- and short-term memory show relationships to decreases in N-methyl-d-aspartate (NMDA) receptor expression, which may involve inflammation. This study was designed to determine effects of an anti-inflammatory drug, ibuprofen, on cognitive function and NMDA receptor expression across aging. Male C57BL/6 mice (ages 5, 14, 20, and 26months) were fed ibuprofen (375ppm) in NIH31 diet or diet alone for 6weeks prior to testing. Behavioral testing using the Morris water maze showed that older mice performed significantly worse than younger in spatial long-term memory, reversal, and short-term memory tasks...
March 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28042872/infralimbic-glun2a-containing-nmda-receptors-modulate-reconsolidation-of-cocaine-self-administration-memory
#13
Madalyn Hafenbreidel, Carolynn Rafa Todd, Devin Mueller
Addiction is characterized by high relapse susceptibility, and relapse can be triggered by drug-associated cues. Cue presentation induces retrieval of the drug-cue memory, which becomes labile and must be reconsolidated into long-term storage. Repeated unpaired cue presentation, however, induces extinction. Cue-reactivity can be reduced by blocking reconsolidation or facilitating extinction, which are mediated by NMDA receptors (NMDArs). However, the role of NMDArs in either process following self-administration is unclear...
January 2, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28027456/immunohistochemical-localization-of-ionotropic-glutamate-receptors-in-the-rat-red-nucleus
#14
Zehra Minbay, Sema Serter Kocoglu, Duygu Gok Yurtseven, Ozhan Eyigor
In this study, we aimed to determine the presence as well as the diverse distribution of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor subunits in the rat red nucleus. Using adult Sprague-Dawley rats as the experimental animals, immunohistochemistry was performed on 30 µm thick coronal brain sections with antibodies against α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (GluA1-4), kainate (GluK1, GluK2/3, and GluK5), and NMDA (GluN1 and GluN2A) receptor subunits. The results showed that all ionotropic glutamate receptor subunits are expressed in the red nucleus...
December 21, 2016: Bosnian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/27986922/cocaine-promotes-coincidence-detection-and-lowers-induction-threshold-during-hebbian-associative-synaptic-potentiation-in-prefrontal-cortex
#15
Hongyu Ruan, Wei-Dong Yao
: Addictive drugs usurp neural plasticity mechanisms that normally serve reward-related learning and memory, primarily by evoking changes in glutamatergic synaptic strength in the mesocorticolimbic dopamine circuitry. Here we show that repeated cocaine exposure in vivo does not alter synaptic strength in the mouse prefrontal cortex during an early period of withdrawal, but instead modifies a Hebbian quantitative synaptic learning rule by broadening the temporal window and lowers the induction threshold for spike timing-dependent LTP (t-LTP)...
December 16, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27916457/molecular-basis-for-subtype-specificity-and-high-affinity-zinc-inhibition-in-the-glun1-glun2a-nmda-receptor-amino-terminal-domain
#16
Annabel Romero-Hernandez, Noriko Simorowski, Erkan Karakas, Hiro Furukawa
Zinc is vastly present in the mammalian brain and controls functions of various cell surface receptors to regulate neurotransmission. A distinctive characteristic of N-methyl-D-aspartate (NMDA) receptors containing a GluN2A subunit is that their ion channel activity is allosterically inhibited by a nano-molar concentration of zinc that binds to an extracellular domain called an amino-terminal domain (ATD). Despite physiological importance, the molecular mechanism underlying the high-affinity zinc inhibition has been incomplete because of the lack of a GluN2A ATD structure...
December 21, 2016: Neuron
https://www.readbyqxmd.com/read/27876530/two-adjacent-phenylalanines-in-the-nmda-receptor-glun2a-subunit-m3-domain-interactively-regulate-alcohol-sensitivity-and-ion-channel-gating
#17
Hong Ren, Yulin Zhao, Man Wu, Donard S Dwyer, Robert W Peoples
The N-methyl-d-aspartate (NMDA) receptor is a key target of ethanol action in the central nervous system. Alcohol inhibition of NMDA receptor function involves small clusters of residues in the third and fourth membrane-associated (M) domains. Previous results from this laboratory have shown that two adjacent positions in the M3 domain, F636 and F637, can powerfully regulate alcohol sensitivity and ion channel gating. In this study, we report that these positions interact with one another in the regulation of both NMDA receptor gating and alcohol action...
March 1, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27857196/step-activation-by-g%C3%AE-q-coupled-gpcrs-opposes-src-regulation-of-nmda-receptors-containing-the-glun2a-subunit
#18
Meng Tian, Jian Xu, Gang Lei, Paul J Lombroso, Michael F Jackson, John F MacDonald
N-methyl-D-aspartate receptors (NMDARs) are necessary for the induction of synaptic plasticity and for the consolidation of learning and memory. NMDAR function is tightly regulated by functionally opposed families of kinases and phosphatases. Herein we show that the striatal-enriched protein tyrosine phosphatase (STEP) is recruited by Gαq-coupled receptors, including the M1 muscarinic acetylcholine receptor (M1R), and opposes the Src tyrosine kinase-mediated increase in the function of NMDARs composed of GluN2A...
November 18, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27847466/glun2a-subunit-containing-nmda-receptors-are-the-preferential-neuronal-targets-of-homocysteine
#19
Dmitry A Sibarov, Polina A Abushik, Rashid Giniatullin, Sergei M Antonov
Homocysteine (HCY) is an endogenous redox active amino acid, best known as contributor to various neurodegenerative disorders. Although it is known that HCY can activate NMDA receptors (NMDARs), the mechanisms of its action on receptors composed of different NMDA receptor subunits remains almost unknown. In this study, using imaging and patch clamp technique in cultured cortical neurons and heterologous expression in HEK293T cells we tested the agonist activity of HCY on NMDARs composed of GluN1 and GluN2A subunits (GluN1/2A receptors) and GluN1 and GluN2B subunits (GluN1/2B receptors)...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27845401/neuroprotection-mediated-through-glun2c-containing-n-methyl-d-aspartate-nmda-receptors-following-ischemia
#20
Connie Chung, John D Marson, Quan-Guang Zhang, Jimok Kim, Wei-Hua Wu, Darrell W Brann, Bo-Shiun Chen
Post-ischemic activation of NMDA receptors (NMDARs) has been linked to NMDAR subunit-specific signaling that mediates pro-survival or pro-death activity. Although extensive studies have been performed to characterize the role of GluN2A and GluN2B following ischemia, there is less understanding regarding the regulation of GluN2C. Here, we show that GluN2C expression is increased in acute hippocampal slices in response to ischemia. Strikingly, GluN2C knockout mice, following global cerebral ischemia, exhibit greater neuronal death in the CA1 area of the hippocampus and reduced spatial working memory compared to wild-type mice...
November 15, 2016: Scientific Reports
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