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Metabotropic glutamate receptor

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https://www.readbyqxmd.com/read/28228527/activation-mechanism-of-the-g-protein-coupled-sweet-receptor-heterodimer-with-sweeteners-and-allosteric-agonists
#1
Soo-Kyung Kim, Yalu Chen, Ravinder Abrol, William A Goddard, Brian Guthrie
The sweet taste in humans is mediated by the TAS1R2/TAS1R3 G protein-coupled receptor (GPCR), which belongs to the class C family that also includes the metabotropic glutamate and γ-aminobutyric acid receptors. We report here the predicted 3D structure of the full-length TAS1R2/TAS1R3 heterodimer, including the Venus Flytrap Domains (VFDs) [in the closed-open (co) active conformation], the cysteine-rich domains (CRDs), and the transmembrane domains (TMDs) at the TM56/TM56 interface. We observe that binding of agonists to VFD2 of TAS1R2 leads to major conformational changes to form a TM6/TM6 interface between TMDs of TAS1R2 and TAS1R3, which is consistent with the activation process observed biophysically on the metabotropic glutamate receptor 2 homodimer...
February 22, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28219342/effects-of-exposure-to-streptococcus-iniae-on-microrna-expression-in-the-head-kidney-of-genetically-improved-farmed-tilapia-oreochromis-niloticus
#2
Jun Qiang, Fanyi Tao, Jie He, Lanyi Sun, Pao Xu, Wenjin Bao
BACKGROUND: Genetically improved farmed tilapia (GIFT, Oreochromis niloticus) are susceptible to infection by Streptococcus iniae when maintained in modern intensive culture systems. GIFT are commercially important fishes that are cultured widely in southern China. The role of microRNAs (miRNAs) in the regulatory response of GIFT to S. iniae infection has been underestimated and has not yet been well studied. Head kidney has an important immune function in teleost fishes. The main aim of this study was to determine the possible function of miRNAs in head kidney of S...
February 20, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28216000/pharmacological-and-molecular-characterization-of-the-positive-allosteric-modulators-of-metabotropic-glutamate-receptor-2
#3
REVIEW
L Lundström, C Bissantz, J Beck, M Dellenbach, T J Woltering, J Wichmann, S Gatti
The metabotropic glutamate receptor 2 (mGlu2) plays an important role in the presynaptic control of glutamate release and several mGlu2 positive allosteric modulators (PAMs) have been under assessment for their potential as antipsychotics. The binding mode of mGlu2 PAMs is better characterized in functional terms while few data are available on the relationship between allosteric and orthosteric binding sites. Pharmacological studies characterizing binding and effects of two different chemical series of mGlu2 PAMs are therefore carried out here using the radiolabeled mGlu2 agonist (3)[H]-LY354740 and mGlu2 PAM (3)[H]-2,2,2-TEMPS...
February 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28212543/metabotropic-glutamate-receptors-as-a-new-therapeutic-target-for-malignant-gliomas
#4
REVIEW
Mery Stefani Leivas Pereira, Fábio Klamt, Chairini Cássia Thomé, Paulo Valdeci Worm, Diogo Losch de Oliveira
Metabotropic glutamate receptors (mGluR) are predominantly involved in maintenance of cellular homeostasis of central nervous system. However, evidences have suggested other roles of mGluR in human tumors. Aberrant mGluR signaling has been shown to participate in transformation and maintenance of various cancer types, including malignant brain tumors. This review intends to summarize recent findings regarding the involvement of mGluR-mediated intracellular signaling pathways in progression, aggressiveness, and recurrence of malignant gliomas, mainly glioblastomas (GBM), highlighting the potential therapeutic applications of mGluR ligands...
February 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28212015/discovery-and-preclinical-characterization-of-3-4-4-chlorophenyl-7-fluoroquinoline-3-yl-sulfonyl-benzonitrile-a-novel-non-acetylenic-metabotropic-glutamate-receptor-5-mglur5-negative-allosteric-modulator-for-psychiatric-indications
#5
János Galambos, Attila Bielik, Mikhail Krasavin, Zoltán Orgován, György Domány, Katalin Nógrádi, Gábor Wágner, György T Balogh, Zoltán Béni, János Koti, Zoltán Szakács, Amrita Bobok, Sándor Kolok, Mónika L Miko-Bakk, Mónika Vastag, Katalin Sághy, Judit Laszy, Attila Sándor Halász, Ottilia Balázs, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keserű
Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as potential pharmacotherapy for a number of psychiatric diseases including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore...
February 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28208727/bioactive-benzofuran-derivatives-from-cortex-mori-radicis-and-their-neuroprotective-and-analgesic-activities-mediated-by-mglur%C3%A2
#6
Ya-Nan Wang, Mao-Feng Liu, Wei-Zhen Hou, Rui-Ming Xu, Jie Gao, An-Qi Lu, Mei-Ping Xie, Lan Li, Jian-Jun Zhang, Ying Peng, Li-Li Ma, Xiao-Liang Wang, Jian-Gong Shi, Su-Juan Wang
Four new benzofuran-type stilbene glycosides and 14 known compounds including 8 benzofuran-type stilbenes and 6 flavonoids were isolated from the traditional Chinese medicine, Cortex Mori Radicis. The new compounds were identified as (9R)-moracin P 3'-O-α-l-arabinopyranoside (1), (9R)-moracin P 9-O-β-d-glucopyranoside (2), (9R)-moracin P 3'-O-β-d-glucopyranoside (3), and (9R)-moracin O 10-O-β-d-glucopyranoside (4) based on the spectroscopic interpretation and chemical analysis. Three benzofuran-type stilbenes, moracin O (5), R (7), and P (8) showed significant neuroprotective activity against glutamate-induced cell death in SK-N-SH cells...
February 8, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28202907/calpain-1-deletion-impairs-mglur-dependent-ltd-and-fear-memory-extinction
#7
Guoqi Zhu, Victor Briz, Jeff Seinfeld, Yan Liu, Xiaoning Bi, Michel Baudry
Recent studies indicate that calpain-1 is required for the induction of long-term potentiation (LTP) elicited by theta-burst stimulation in field CA1 of hippocampus. Here we determined the contribution of calpain-1 in another type of synaptic plasticity, the long-term depression (LTD) elicited by activation of type-I metabotropic glutamate receptors (mGluR-LTD). mGluR-LTD was associated with calpain-1 activation following T-type calcium channel opening, and resulted in the truncation of a regulatory subunit of PP2A, B56α...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28196513/metabotropic-glutamate-receptor-5-may-be-involved-in-macrophage-plasticity
#8
Lali Shanshiashvili, Elene Tsitsilashvili, Nino Dabrundashvili, Irine Kalandadze, David Mikeladze
BACKGROUND: Macrophages are a functionally heterogeneous cell population and depending on microenvironments they polarize in two main groups: M1 and M2. Glutamic acid and glutamate receptors may participate in the regulation of macrophage plasticity. To investigate the role of glutamatergic systems in macrophages physiology, we performed the transfection of mGluR5 cDNAs into RAW-264.7 cells. RESULTS: Comparative analysis of modified (RAW-mGluR5 macrophages) and non-modified macrophages (RAW-macrophages) has shown that the RAW-mGluR5 macrophages absorbed more glutamate than control cells and the amount of intracellular glutamate correlated with the expression of excitatory amino acid transporters -2 (EAAT-2)...
February 14, 2017: Biological Research
https://www.readbyqxmd.com/read/28192424/spatial-separation-of-two-different-pathways-accounting-for-the-generation-of-calcium-signals-in-astrocytes
#9
Franziska Oschmann, Konstantin Mergenthaler, Evelyn Jungnickel, Klaus Obermayer
Astrocytes integrate and process synaptic information and exhibit calcium (Ca2+) signals in response to incoming information from neighboring synapses. The generation of Ca2+ signals is mostly attributed to Ca2+ release from internal Ca2+ stores evoked by an elevated metabotropic glutamate receptor (mGluR) activity. Different experimental results associated the generation of Ca2+ signals to the activity of the glutamate transporter (GluT). The GluT itself does not influence the intracellular Ca2+ concentration, but it indirectly activates Ca2+ entry over the membrane...
February 13, 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28186680/the-group-ii-metabotropic-glutamate-receptor-agonist-ly354740-and-the-d2-receptor-antagonist-haloperidol-reduce-locomotor-hyperactivity-but-fail-to-rescue-spatial-working-memory-in-glua1-knockout-mice
#10
Thomas Boerner, Alexei Bygrave, Jingkai Chen, Anushka Fernando, Stephanie Jackson, Chris Barkus, Rolf Sprengel, Peter H Seeburg, Paul J Harrison, Gary Gilmour, David M Bannerman, David J Sanderson
Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies...
February 10, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28181188/atorvastatin-promotes-cytotoxicity-and-reduces-migration-and-proliferation-of-human-a172-glioma-cells
#11
Karen A Oliveira, Tharine Dal-Cim, Flávia G Lopes, Fabiana K Ludka, Cláudia B Nedel, Carla I Tasca
Malignant gliomas have resistance mechanisms to chemotherapy that enable tumor invasiveness and aggressiveness. Alternative therapies in cancer treatment, as statins, have been suggested to decrease proliferation, inhibit cell migration, and induce cell death. The aim of this study was to evaluate the effect of atorvastatin (ATOR) on cell viability, migration, proliferation, apoptosis, and autophagy in A172 human glioma cells. Temozolomide (TMZ), a chemotherapic used to glioma treatment, was tested as a comparison to cytotoxic effects on gliomas...
February 8, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28179473/dynamic-regulation-of-homer-binding-to-group-i-mglurs-by-preso1-and-converging-kinase-cascades
#12
Jia-Hua Hu, Paul F Worley, Paul Kammermeier
In rat sympathetic neurons from the superior cervical ganglia (SCG) expressing metabotropic glutamate receptors (mGluRs) 1 or 5, overexpression of scaffolding Homer proteins, which bind to a Homer ligand in their C-termini, cause receptor clustering and uncoupling from ion channel modulation. In the absence of recombinant Homer protein overexpression, uncoupling of mGluRs from voltage dependent channels can be induced by expression of Preso1, an adaptor of proline directed kinases that phosphorylates the Homer ligand and recruits binding of endogenous Homer proteins...
February 8, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28177520/broad-spectrum-efficacy-with-ly2969822-an-oral-prodrug-of-metabotropic-glutamate-2-3-mglu2-3-receptor-agonist-ly2934747-in-rodent-pain-models
#13
Michael P Johnson, Mark A Muhlhauser, Eric S Nisenbaum, Rosa M A Simmons, Beth M Forster, Kelly L Knopp, Lijuan Yang, Denise Morrow, Dominic L Li, Jeffrey D Kennedy, Steven Swanson, James A Monn
BACKGROUND AND PURPOSE: A body of evidence suggests activation of metabotropic glutamate 2/3 (mGlu2/3 ) receptors would be an effective analgesic in chronic pain conditions. Thus, the analgesic properties of a novel mGlu2/3 receptor agonist prodrug were investigated. EXPERIMENTAL APPROACH: After oral absorption, the prodrug LY2969822 rapidly converts to the brain penetrant, potent, and subtype-selective mGlu2/3 receptor agonist LY2934747. Behavioral assessments of allodynia, hyperalgesia, or nocifensive behaviors in preclinical pain models were determined after administration of LY2969822 of 0...
February 8, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28176276/maintained-ltp-and-memory-are-lost-by-zn-2-influx-into-dentate-granule-cells-but-not-ca-2-influx
#14
Atsushi Takeda, Haruna Tamano, Marie Hisatsune, Taku Murakami, Hiroyuki Nakada, Hiroaki Fujii
The idea that maintained LTP and memory are lost by either increase in intracellular Zn(2+) in dentate granule cells or increase in intracellular Ca(2+) was examined to clarify significance of the increases induced by excess synapse excitation. Both maintained LTP and space memory were impaired by injection of high K(+) into the dentate gyrus, but rescued by co-injection of CaEDTA, which blocked high K(+)-induced increase in intracellular Zn(2+) but not high K(+)-induced increase in intracellular Ca(2+). High K(+)-induced disturbances of LTP and intracellular Zn(2+) are rescued by co-injection of 6-cyano-7-nitroquinoxakine-2,3-dione, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, but not by co-injection of blockers of NMDA receptors, metabotropic glutamate receptors, and voltage-dependent calcium channels...
February 7, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28167616/towards-trans-diagnostic-mechanisms-in-psychiatry-neurobehavioral-profile-of-rats-with-a-loss-of-function-point-mutation-in-the-dopamine-transporter-gene
#15
Valentina Vengeliene, Anton Bespalov, Martin Roßmanith, Sandra Horschitz, Stefan Berger, Ana L Relo, Hamid R Noori, Peggy Schneider, Thomas Enkel, Dusan Bartsch, Miriam Schneider, Berthold Behl, Anita C Hansson, Patrick Schloss, Rainer Spanagel
The Research Domain Criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here we used a new genetic rat model with a loss of function point mutation in the dopamine transporter (DAT) gene (Slc6a3_N157K) to systematically study the RDoC matrix (www.nimh.nih.gov/research-priorities/rdoc/constructs/rdoc-matrix.shtml). First, we examined the impact of the Slc6a3_N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains - negative and positive valence systems, cognitive, social, and in arousal/regulatory systems...
February 6, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28166368/efficacy-of-mglu2-positive-allosteric-modulators-alone-and-in-combination-with-levetiracetam-in-the-mouse-6-hz-model-of-psychomotor-seizures
#16
Cameron S Metcalf, Brian D Klein, Misty D Smith, Tim Pruess, Marc Ceusters, Hilde Lavreysen, Stefan Pype, Nancy Van Osselaer, Roy Twyman, H Steve White
OBJECTIVE: The metabotropic glutamate receptor subtype 2 (mGlu2 ) possesses both orthosteric and allosteric modulatory sites, are expressed in the frontal cortex and limbic structures, and can affect excitatory synaptic transmission. Therefore, mGlu2 is a potential therapeutic target in the treatment of epilepsy. The present study seeks to evaluate the anticonvulsant potential of mGlu2 -acting compounds. METHODS: The anticonvulsant efficacy of two selective mGlu2 -positive allosteric modulators (PAMs) (JNJ-42153605 and JNJ-40411813/ADX71149) and one mGlu2/3 receptor agonist (LY404039) were evaluated alone and in combination with the antiseizure drug levetiracetam (LEV) in the mouse 6 Hz model...
February 6, 2017: Epilepsia
https://www.readbyqxmd.com/read/28159646/metabotropic-glutamate-receptor-2-inhibits-thalamically-driven-glutamate-and-dopamine-release-in-the-dorsal-striatum
#17
Kari A Johnson, Yolanda Mateo, David M Lovinger
The striatum plays critical roles in action control and cognition, and activity of striatal neurons is driven by glutamatergic input. Inhibition of glutamatergic inputs to projection neurons and interneurons of the striatum by presynaptic G protein-coupled receptors (GPCRs) stands to modulate striatal output and striatum-dependent behaviors. Despite knowledge that a substantial number of glutamatergic inputs to striatal neurons originate in the thalamus, most electrophysiological studies assessing GPCR modulation do not differentiate between effects on corticostriatal and thalamostriatal transmission, and synaptic inhibition is frequently assumed to be mediated by activation of GPCRs on corticostriatal terminals...
January 31, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28154077/homer1a-drives-homeostatic-scaling-down-of-excitatory-synapses-during-sleep
#18
Graham H Diering, Raja S Nirujogi, Richard H Roth, Paul F Worley, Akhilesh Pandey, Richard L Huganir
Sleep is an essential process that supports learning and memory by acting on synapses through poorly understood molecular mechanisms. Using biochemistry, proteomics, and imaging in mice, we find that during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors mGluR1/5...
February 3, 2017: Science
https://www.readbyqxmd.com/read/28149957/illuminating-phenylazopyridines-to-photoswitch-metabotropic-glutamate-receptors-from-the-flask-to-the-animals
#19
Xavier Gómez-Santacana, Silvia Pittolo, Xavier Rovira, Marc Lopez, Charleine Zussy, James A R Dalton, Adèle Faucherre, Chris Jopling, Jean-Philippe Pin, Francisco Ciruela, Cyril Goudet, Jesús Giraldo, Pau Gorostiza, Amadeu Llebaria
Phenylazopyridines are photoisomerizable compounds with high potential to control biological functions with light. We have obtained a series of phenylazopyridines with light dependent activity as negative allosteric modulators (NAM) of metabotropic glutamate receptor subtype 5 (mGlu5). Here we describe the factors needed to achieve an operational molecular photoisomerization and its effective translation into in vitro and in vivo receptor photoswitching, which includes zebrafish larva motility and the regulation of the antinociceptive effects in mice...
January 25, 2017: ACS Central Science
https://www.readbyqxmd.com/read/28137639/acid-sensing-ion-channel-1a-is-required-for-mglu-receptor-dependent-long-term-depression-in-the-hippocampus
#20
D Mango, E Braksator, G Battaglia, S Marcelli, N B Mercuri, M Feligioni, F Nicoletti, Z I Bashir, R Nisticò
Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na(+) channel superfamily, are widely distributed in the mammalian nervous system. ASIC1a is highly permeable to Ca(2+) and are thought to be important in a variety of physiological processes, including synaptic plasticity, learning and memory. To further understand the role of ASIC1a in synaptic transmission and plasticity, we investigated metabotropic glutamate (mGlu) receptor-dependent long-term depression (LTD) in the hippocampus. We found that ASIC1a channels mediate a component of LTD in P30-40 animals, since the ASIC1a selective blocker psalmotoxin-1 (PcTx1) reduced the magnitude of LTD induced by application of the group I mGlu receptor agonist (S)-3,5-Dihydroxyphenylglycine (DHPG) or induced by paired-pulse low frequency stimulation (PP-LFS)...
January 27, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
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