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GluN2B

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https://www.readbyqxmd.com/read/28731405/pro-death-nmda-receptor-signaling-is-promoted-by-the-glun2b-c-terminus-independently-of-dapk1
#1
Jamie McQueen, Tomas J Ryan, Sean McKay, Katie Fm Marwick, Paul E Baxter, Sarah M Carpanini, Thomas M Wishart, Thomas H Gillingwater, Jean C Manson, David Ja Wyllie, Seth Gn Grant, Barry McColl, Noboru Komiyama, Giles E Hardingham
Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by DAPK1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by DAPK1 deficiency in vitro or following ischemia in vivo...
July 21, 2017: ELife
https://www.readbyqxmd.com/read/28720858/gsk-3%C3%AE-deletion-in-dentate-gyrus-excitatory-neuron-impairs-synaptic-plasticity-and-memory
#2
Enjie Liu, Ao-Ji Xie, Qiuzhi Zhou, Mengzhu Li, Shujuan Zhang, Shihong Li, Weijin Wang, Xiaochuan Wang, Qun Wang, Jian-Zhi Wang
Increasing evidence suggests that glycogen synthase kinase-3β (GSK-3β) plays a crucial role in neurodegenerative/psychiatric disorders, while pan-neural knockout of GSK-3β also shows detrimental effects. Currently, the function of GSK-3β in specific type of neurons is elusive. Here, we infused AAV-CaMKII-Cre-2A-eGFP into GSK-3β(lox/lox) mice to selectively delete the kinase in excitatory neurons of hippocampal dentate gyrus (DG), and studied the effects on cognitive/psychiatric behaviors and the molecular mechanisms...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28719605/extracellular-phosphorylation-of-a-receptor-tyrosine-kinase-controls-synaptic-localization-of-nmda-receptors-and-regulates-pathological-pain
#3
Kenji Hanamura, Halley R Washburn, Sean I Sheffler-Collins, Nan L Xia, Nathan Henderson, Dipti V Tillu, Shayne Hassler, Daniel S Spellman, Guoan Zhang, Thomas A Neubert, Theodore J Price, Matthew B Dalva
Extracellular phosphorylation of proteins was suggested in the late 1800s when it was demonstrated that casein contains phosphate. More recently, extracellular kinases that phosphorylate extracellular serine, threonine, and tyrosine residues of numerous proteins have been identified. However, the functional significance of extracellular phosphorylation of specific residues in the nervous system is poorly understood. Here we show that synaptic accumulation of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs) and pathological pain are controlled by ephrin-B-induced extracellular phosphorylation of a single tyrosine (p*Y504) in a highly conserved region of the fibronectin type III (FN3) domain of the receptor tyrosine kinase EphB2...
July 2017: PLoS Biology
https://www.readbyqxmd.com/read/28716964/a-glun2b-selective-nmdar-antagonist-reverses-synapse-loss-and-cognitive-impairment-produced-by-the-hiv-1-protein-tat
#4
Jonathan D Raybuck, Nicholas J Hargus, Stanley A Thayer
HIV-associated neurocognitive disorder (HAND) affects approximately half of HIV-infected patients. Loss of synaptic connections is a hallmark of many neurocognitive disorders, including HAND. The HIV-1 protein transactivator of transcription (Tat) disrupts synaptic connections both in vitro and in vivo and has been linked to impaired neurocognitive function in humans. In vitro studies have shown that ifenprodil, an antagonist selective for GluN2B-containing NMDARs, reverses synapse loss when applied after Tat...
July 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28704758/deconstruction-reconstruction-approach-to-analyze-the-essential-structural-elements-of-tetrahydro-3-benzazepine-based-antagonists-of-glun2b-subunit-containing-nmda-receptors
#5
Sougata Dey, Louisa Temme, Julian A Schreiber, Dirk Schepmann, Bastian Frehland, Kirstin Lehmkuhl, Nathalie Strutz-Seebohm, Guiscard Seebohm, Bernhard Wünsch
The role of the phenolic and benzylic OH moieties for the interaction of tetrahydro-3-benzazepine-1,7-diol 3d with GluN2B subunit containing NMDA receptors was analyzed by their stepwise removal. Elimination of trifluormethanesulfinate from 10 and 13 represent the key steps in the synthesis. Removal of phenolic OH moiety led to 5-fold reduced GluN2B affinity of 4d compared with 3d. Additional removal of the benzylic OH moiety (5d) resulted in further reduced GluN2B affinity but increased σ1 and σ2 affinities...
July 1, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28688852/cdkl5-controls-postsynaptic-localization-of-glun2b-containing-nmda-receptors-in-the-hippocampus-and-regulates-seizure-susceptibility
#6
Kosuke Okuda, Shizuka Kobayashi, Masahiro Fukaya, Aya Watanabe, Takuto Murakami, Mai Hagiwara, Tempei Sato, Hiroe Ueno, Narumi Ogonuki, Sayaka Komano-Inoue, Hiroyuki Manabe, Masahiro Yamaguchi, Atsuo Ogura, Hiroshi Asahara, Hiroyuki Sakagami, Masashi Mizuguchi, Toshiya Manabe, Teruyuki Tanaka
Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA...
July 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28682239/physiological-and-pathophysiological-control-of-synaptic-glun2b-nmda-receptors-by-the-c-terminal-domain-of-amyloid-precursor-protein
#7
Paula A Pousinha, Xavier Mouska, Elisabeth F Raymond, Carole Gwizdek, Ghien Dhib, Gwenola Poupon-Silvestre, Laure-Emmanuelle Zaragosi, Camilla Giudici, Ingrid Bethus, Emilie Pacary, Michael Willem, Hélène Marie
The amyloid precursor protein (APP) harbors physiological roles at synapses and is central to Alzheimer's disease (AD) pathogenesis. Evidence suggests that APP intracellular domain (AICD) could regulate synapse function, but the underlying molecular mechanisms remain unknown. We addressed AICD actions at synapses, per se, combining in-vivo AICD expression, ex-vivo AICD delivery or APP knock-down by in utero electroporation of shRNAs with whole-cell electrophysiology. We report a critical physiological role of AICD in controlling GluN2B-containing NMDA receptors (NMDARs) at immature excitatory synapses, via a transcription-dependent mechanism...
July 6, 2017: ELife
https://www.readbyqxmd.com/read/28663723/huntingtin-interacting-protein-1-related-protein-plays-a-critical-role-in-dendritic-development-and-excitatory-synapse-formation-in-hippocampal-neurons
#8
Lin Peng, Qian Yang, Xingxing Xu, Yonglan Du, Yu Wu, Xiaofang Shi, Junyu Xu, Lijun Zhu, Jianhong Luo
Huntingtin-interacting protein 1-related (HIP1R) protein is considered to be an endocytic adaptor protein like the other two members of the Sla2 family, Sla2p and HIP1. They all contain homology domains responsible for the binding of clathrin, inositol lipids and F-actin. Previous studies have revealed that HIP1R is highly expressed in different regions of the mouse brain and localizes at synaptic structures. However, the function of HIP1R in the nervous system remains unknown. In this study, we investigated HIP1R function in cultured rat hippocampal neurons using an shRNA knockdown approach...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28658619/peripheral-sensory-deprivation-restores-critical-period-like-plasticity-to-adult-somatosensory-thalamocortical-inputs
#9
Seungsoo Chung, Ji-Hyun Jeong, Sukjin Ko, Xin Yu, Young-Hwan Kim, John T R Isaac, Alan P Koretsky
Recent work has shown that thalamocortical (TC) inputs can be plastic after the developmental critical period has closed, but the mechanism that enables re-establishment of plasticity is unclear. Here, we find that long-term potentiation (LTP) at TC inputs is transiently restored in spared barrel cortex following either a unilateral infra-orbital nerve (ION) lesion, unilateral whisker trimming, or unilateral ablation of the rodent barrel cortex. Restoration of LTP is associated with increased potency at TC input and reactivates anatomical map plasticity induced by whisker follicle ablation...
June 27, 2017: Cell Reports
https://www.readbyqxmd.com/read/28633291/p2x7-receptors-drive-spine-synapse-plasticity-in-the-learned-helplessness-model-of-depression
#10
L Otrokocsi, Á Kittel, B Sperlágh
Background: Major depressive disorder is characterized by structural and functional abnormalities of cortical and limbic brain areas, including a decrease in spine synapse number in the dentate gyrus (DG) of the hippocampus. Recent studies highlighted that both genetic and pharmacological invalidation of the purinergic P2X7 receptor (P2rx7) leads to antidepressant-like phenotype in animal experiments, however, the impact of P2rx7 on depression-related structural changes in the hippocampus is not clarified yet...
June 13, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28614711/dapk1-mediates-ltd-by-making-camkii-glun2b-binding-ltp-specific
#11
Dayton J Goodell, Vincent Zaegel, Steven J Coultrap, Johannes W Hell, K Ulrich Bayer
The death-associated protein kinase 1 (DAPK1) is a potent mediator of neuronal cell death. Here, we find that DAPK1 also functions in synaptic plasticity by regulating the Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII). CaMKII and T286 autophosphorylation are required for both long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory, and cognition. T286-autophosphorylation induces CaMKII binding to the NMDA receptor (NMDAR) subunit GluN2B, which mediates CaMKII synaptic accumulation during LTP...
June 13, 2017: Cell Reports
https://www.readbyqxmd.com/read/28602919/the-fine-tuning-of-retinocollicular-topography-depends-on-reelin-signaling-during-early-postnatal-development-of-the-rat-visual-system
#12
Rachel Antonioli-Santos, Bruna Lanzillotta-Mattos, Cecília Hedin-Pereira, Claudio Alberto Serfaty
During postnatal development, neural circuits are extremely dynamic and develop precise connection patterns that emerge as a result of the elimination of synaptic terminals, a process instructed by molecular cues and patterns of electrical activity. In the rodent visual system, this process begins during the first postnatal week and proceeds during the second and third postnatal weeks as spontaneous retinal activity and finally use-dependent fine tuning takes place. Reelin is a large extracellular matrix glycoprotein able to affect several steps of brain development, from neuronal migration to the maturation of dendritic spines and use-dependent synaptic development...
June 8, 2017: Neuroscience
https://www.readbyqxmd.com/read/28598327/co-agonists-differentially-tune-glun2b-nmda-receptor-trafficking-at-hippocampal-synapses
#13
Joana S Ferreira, Thomas Papouin, Laurent Ladépêche, Andrea Yao, Valentin C Langlais, Delphine Bouchet, Jérôme Dulong, Jean-Pierre Mothet, Silvia Sacchi, Loredano Pollegioni, Pierre Paoletti, Stéphane Henri Richard Oliet, Laurent Groc
The subunit composition of synaptic NMDA receptors (NMDAR), such as the relative content of GluN2A- and GluN2B-containing receptors, greatly influences the glutamate synaptic transmission. Receptor co-agonists, glycine and D-serine, have intriguingly emerged as potential regulators of the receptor trafficking in addition to their requirement for its activation. Using a combination of single-molecule imaging, biochemistry and electrophysiology, we show that glycine and D-serine relative availability at rat hippocampal glutamatergic synapses regulate the trafficking and synaptic content of NMDAR subtypes...
June 9, 2017: ELife
https://www.readbyqxmd.com/read/28594961/pirb-regulates-asymmetries-in-hippocampal-circuitry
#14
Hikari Ukai, Aiko Kawahara, Keiko Hirayama, Matthew Julian Case, Shotaro Aino, Masahiro Miyabe, Ken Wakita, Ryohei Oogi, Michiyo Kasayuki, Shihomi Kawashima, Shunichi Sugimoto, Kanako Chikamatsu, Noritaka Nitta, Tsuneyuki Koga, Ryuichi Shigemoto, Toshiyuki Takai, Isao Ito
Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRε2 (also known as NR2B, GRIN2B or GluN2B). By examining the synaptic distribution of ε2 subunits, we previously found that β2-microglobulin-deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI) proteins, do not exhibit circuit asymmetry...
2017: PloS One
https://www.readbyqxmd.com/read/28594440/calcium-signalling-in-medial-intercalated-cell-dendrites-and-spines
#15
Cornelia Strobel, Robert K P Sullivan, Peter Stratton, Pankaj Sah
KEY POINTS: Dendritic and spine calcium imaging in combination with electrophysiology in acute slices revealed that in medial intercalated cells of the amygdala: Action potentials back-propagate into the dendritic tree, but due to the presence of voltage-dependent potassium channels, probably Kv4.2 channels, attenuate over distance. A mixed population of AMPA receptors with rectifying and linear I-V relations are present at individual spines of a single neuron. Decay kinetics and pharmacology suggest tri-heteromeric NMDA receptors at basolateral-intercalated cell synapses...
June 8, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28588488/antinociceptive-activity-of-borreria-verticillata-in-vivo-and-in-silico-studies
#16
Rosa H M Silva, Nathália de Fátima M Lima, Alberto J O Lopes, Cleydlenne C Vasconcelos, José W C de Mesquita, Ludmilla S S de Mesquita, Fernando C V M Lima, Maria N de S Ribeiro, Ricardo M Ramos, Maria do Socorro de S Cartágenes, João B S Garcia
Borreria verticillata (L.) G. Mey. known vassourinha has antibacterial, antimalarial, hepatoprotective, antioxidative, analgesic, and anti-inflammatory, however, its antinociceptive action requires further studies. Aim of the study evaluated the antinociceptive activity of B. verticillata hydroalcoholic extract (EHBv) and ethyl acetate fraction (FAc) by in vivo and in silico studies. In vivo assessment included the paw edema test, writhing test, formalin test and tail flick test. Wistar rats and Swiss mice were divided into 6 groups and given the following treatments oral: 0...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28588066/identification-of-aicp-as-a-glun2c-selective-nmda-receptor-superagonist-at-the-glun1-glycine-site
#17
Maja Jessen, Kristen Frederiksen, Feng Yi, Rasmus P Clausen, Kasper B Hansen, Hans Brauner-Osborne, Paul Kilburn, Anders Damholt
NMDA-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention as therapeutic targets. In this regard, administration of D-cycloserine (DCS), which is a glycine site NMDA receptor agonist, can enhance extinction of conditioned fear responses. The intriguing behavioral effects of DCS have been linked to its unique pharmacological profile among NMDA receptor subtypes (GluN1/2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared to glycine and a partial agonist at GluN2B-containing receptors...
June 6, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28586221/the-structure-activity-relationship-of-a-tetrahydroisoquinoline-class-of-n-methyl-d-aspartate-receptor-modulators-that-potentiates-glun2b-containing-n-methyl-d-aspartate-receptors
#18
Katie L Strong, Matthew P Epplin, John Bacsa, Christopher J Butch, Pieter B Burger, David S Menaldino, Stephen F Traynelis, Dennis C Liotta
We have identified a series of positive allosteric NMDA receptor (NMDAR) modulators derived from a known class of GluN2C/D-selective tetrahydroisoquinoline analogues that includes CIQ. The prototypical compound of this series contains a single isopropoxy moiety in place of the two methoxy substituents present in CIQ. Modifications of this isopropoxy-containing scaffold led to the identification of analogues with enhanced activity at the GluN2B subunit. We identified molecules that potentiate the response of GluN2B/GluN2C/GluN2D, GluN2B/GluN2C, and GluN2C/GluN2D-containing NMDARs to maximally effective concentrations of agonist...
June 26, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28585567/role-of-src-family-kinases-in-bdnf-mediated-suppression-of-cocaine-seeking-and-prevention-of-cocaine-induced-erk-glun2a-and-glun2b-dephosphorylation-in-the-prelimbic-cortex
#19
Sarah M Barry, Jacqueline F McGinty
Models of relapse have demonstrated that neuroadaptations in reward circuits following cocaine self-administration (SA) underlie reinstatement of drug-seeking. Dysregulation of the pathway from the prelimbic (PrL) cortex to the nucleus accumbens is implicated in reinstatement. A single BDNF infusion into the PrL cortex following a final cocaine SA session results in attenuation of reinstatement of cocaine-seeking. Inhibiting BDNF's receptor, TrkB, ERK/MAP kinase activation, or NMDA receptors blocks this attenuating effect, indicating that the interaction between glutamate-mediated synaptic activity and TrkB signaling is imperative to BDNF's suppressive effect on drug-seeking...
June 6, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28582391/all-atom-nmda-receptor-transmembrane-domain-model-development-and-simulations-in-lipid-bilayers-and-water
#20
Samaneh Mesbahi-Vasey, Lea Veras, Michael Yonkunas, Jon W Johnson, Maria G Kurnikova
N-methyl-d-aspartate receptors (NMDARs) are members of the ionotropic glutamate receptor family that mediate excitatory synaptic transmission in the central nervous system. The channels of NMDARs are permeable to Ca2+ but blocked by Mg2+, distinctive properties that underlie essential brain processes such as induction of synaptic plasticity. However, due to limited structural information about the NMDAR transmembrane ion channel forming domain, the mechanism of divalent cation permeation and block is understood poorly...
2017: PloS One
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