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Metabotropic glutamate receptor

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https://www.readbyqxmd.com/read/28738332/neuroprogression-and-immune-activation-in-major-depressive-disorder
#1
Jeffrey H Meyer
Traditionally, the neurobiology of major depressive disorder (MDD) has been largely considered from the perspective of the state of major depressive episodes (MDE) versus being in remission, but the current accumulation of disease markers, largely acquired cross-sectionally, is strongly suggestive of neuroprogressive aspects of MDD. This chapter focuses on the changes in disease markers involved in the reorganization of the nervous system in MDD, including the translocator protein (TSPO; an index of microglial activation), glial fibrillary acidic protein (GFAP; an index of astroglial activation), [11C]harmine (a marker of monoamine oxidase A; MAO-A), and several other indices (metabotropic glutamate receptor 5 [mGluR5], excitatory amino acid transporters, and magnetic resonance imaging spectroscopy measurements) of glutamate dysregulation...
2017: Modern Trends in Pharmacopsychiatry
https://www.readbyqxmd.com/read/28733356/steady-state-free-ca2-in-astrocytes-is-decreased-by-experience-and-impacts-arteriole-tone
#2
Eslam M F Mehina, Ciaran Murphy-Royal, Grant R Gordon
Astrocytes can control basal synaptic strength and arteriole tone via their resting Ca2+ activity. However, whether resting astrocyte Ca2+ can adjust to a new steady-state level, with an impact on surrounding brain cells, remains unknown. Using two-photon Ca2+ imaging in male rat acute brain slices of the somatosensory neocortex, we found that theta burst neural activity produced an unexpected long-lasting reduction in astrocyte free Ca2+ in the soma and endfeet. The drop in intracellular Ca2+ was attenuated by antagonists targeting multiple ionotropic and metabotropic glutamate receptors, and intracellular cascades involved Ca2+ stores and nitric oxide...
July 21, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28727040/genome-wide-association-studies-and-meta-analysis-reveal-novel-quantitative-trait-loci-and-pleiotropic-loci-for-swine-head-related-traits
#3
H Chen, T Huang, Z Zhang, B Yang, C Jiang, J Wu, Z Zhou, H Zheng, W Xin, M Huang, M Zhang, C Chen, J Ren, H Ai, L Huang
The pig is an important domestic animal that provides a larger amount of meat and serves as a biomedical animal model for human. Head and facial features are closely linked to identity recognition in mammal communication. To uncover the genetic architecture of swine head and facial features, we constructed 5 experimental pig populations and accurately measured 10 traits related to head and facial features, for which genome-wide association studies and meta-analysis were later carried out. As a result, we identified a total of 24 loci harboring 437 SNP on 8 swine chromosomes (SSC) that surpassed suggestively significant levels, of which 17 loci on 6 chromosomes exceeded the 5% genome-wide significance thresholds...
June 2017: Journal of Animal Science
https://www.readbyqxmd.com/read/28726484/annals-express-experience-with-newer-central-nervous-system-autoantibodies
#4
Abid Karim, Saiju Jacob
In the last decade, a large number of neuronal cell-surface antibodies have been described which are responsible for a range of neuroimmunological central nervous system disorders. Unlike the paraneoplastic antibodies which target intracellular antigens, these antibodies appear to be pathogenic and hence identification and prompt treatment can make a substantial impact on clinical outcomes of these patients. We review the common antibodies against the ionotropic Glutamate receptors (NMDAR, AMPAR), metabotropic Glutamate receptors (mGluR1 and mGluR5), voltage gated potassium channel-complex proteins (LGI1, CASPR2), and other antibodies targeted against Glycine receptor, Glutamic acid decarboxylase (GAD), Gamma Amino Butyric Acid B (GABAB), Dopamine-2-receptor (D2R) and Dipeptidyl-peptidase-like protein 6 (DPPX)...
January 1, 2017: Annals of Clinical Biochemistry
https://www.readbyqxmd.com/read/28718992/melatonin-impedes-tet1-dependent-mglur5-promoter-demethylation-to-relieve-pain
#5
Ming-Chun Hsieh, Yu-Cheng Ho, Cheng-Yuan Lai, Dylan Chou, Hsueh-Hsiao Wang, Gin-Den Chen, Tzer-Bin Lin, Hsien-Yu Peng
Melatonin (N-acetyl-5-methoxytryptamine)/MT2 receptor-dependent epigenetic modification represents a novel pathway in the treatment of neuropathic pain. Because spinal ten-eleven translocation methylcytosine dioxygenase 1 (Tet1)-dependent epigenetic demethylation has recently been linked to pain hypersensitivity, we hypothesized that melatonin/MT2-dependent analgesia involves spinal Tet1-dependent demethylation. Here, we showed that spinal Tet1 gene transfer by intrathecal delivery of Tet1-encoding vectors to naïve rats produced profound and long-lasting nociceptive hypersensitivity...
July 18, 2017: Journal of Pineal Research
https://www.readbyqxmd.com/read/28716937/altered-metabotropic-glutamate-receptor-5-markers-in-ptsd-in-vivo-and-postmortem-evidence
#6
Sophie E Holmes, Matthew J Girgenti, Margaret T Davis, Robert H Pietrzak, Nicole DellaGioia, Nabeel Nabulsi, David Matuskey, Steven Southwick, Ronald S Duman, Richard E Carson, John H Krystal, Irina Esterlis
Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [(18)F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs...
July 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28711710/comparison-of-the-role-of-metabotropic-glutamate-receptor-subtype-1-in-developmental-refinement-of-neuronal-connectivity-between-the-cerebellum-and-the-sensory-thalamus
#7
REVIEW
Madoka Narushima
Developmental refinement of neuronal connectivity is crucial for proper brain function. In the early phase of development, input fibers arrive at their target areas guided by specific molecular cues and form abundant immature synapses. Then, functionally important synapses are preserved and strengthened by neural activity while unnecessary synapses are eliminated. Afferent synapses in the sensory thalamus, such as from retina to lateral geniculate nucleus, and climbing fiber (CF)-Purkinje cell (PC) synapses in the cerebellum are valuable models for studying this developmental refinement of synaptic connectivity because only a limited number of input fibers innervate a given postsynaptic thalamocortical (TC) neuron or PC...
July 12, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28704052/discovery-and-kinetic-profiling-of-7-aryl-1-2-4-triazolo-4-3-a-pyridines-positive-allosteric-modulators-of-the-metabotropic-glutamate-receptor-2
#8
Maarten L J Doornbos, José María Cid, Jordi Haubrich, Alexandro Nunes, Jasper W van de Sande, Sophie C Vermond, Thea Mulder-Krieger, Andrés A Trabanco, Abdellah Ahnaou, Wilhelmus H Drinkenburg, Hilde Lavreysen, Laura H Heitman, Adriaan P IJzerman, Gary Tresadern
We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters kon, koff and residence time (RT) were determined. The PAMs showed various kinetic profiles; kon values ranged over two orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant kon was linearly correlated to affinity. Evaluation of a short, medium and long RT compound in a label-free assay indicated a correlation between RT and functional effect...
July 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28700935/deletion-of-type-2-metabotropic-glutamate-receptor-decreases-sensitivity-to-cocaine-reward-in-rats
#9
Hong-Ju Yang, Hai-Ying Zhang, Guo-Hua Bi, Yi He, Jun-Tao Gao, Zheng-Xiong Xi
Cocaine users show reduced expression of the metabotropic glutamate receptor (mGluR2), but it is not clear whether this is a predisposing trait for addiction or a consequence of drug exposure. In this study, we found that a nonsense mutation at the mGluR2 gene decreased mGluR2 expression and altered the seeking and taking of cocaine. mGluR2 mutant rats show reduced sensitivity to cocaine reward, requiring more cocaine to reach satiation when it was freely available and ceasing their drug-seeking behavior sooner than controls when the response requirement was increased...
July 11, 2017: Cell Reports
https://www.readbyqxmd.com/read/28696429/glud1-linked-to-schizophrenia-controls-the-burst-firing-of-dopamine-neurons
#10
N Benamer, F Marti, R Lujan, R Hepp, T G Aubier, A A M Dupin, G Frébourg, S Pons, U Maskos, P Faure, Y A Hay, B Lambolez, L Tricoire
Human mutations of the GRID1 gene encoding the orphan delta1 glutamate receptor-channel (GluD1) are associated with schizophrenia but the explicit role of GluD1 in brain circuits is unknown. Based on the known function of its paralog GluD2 in cerebellum, we searched for a role of GluD1 in slow glutamatergic transmission mediated by metabotropic receptor mGlu1 in midbrain dopamine neurons, whose dysfunction is a hallmark of schizophrenia. We found that an mGlu1 agonist elicits a slow depolarizing current in HEK cells co-expressing mGlu1 and GluD1, but not in cells expressing mGlu1 or GluD1 alone...
July 11, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28694498/analysis-of-positive-and-negative-allosteric-modulation-in-metabotropic-glutamate-receptors-4-and-5-with-a-dual-ligand
#11
James A R Dalton, Jean-Philippe Pin, Jesús Giraldo
As class C GPCRs and regulators of synaptic activity, human metabotropic glutamate receptors (mGluRs) 4 and 5 are prime targets for allosteric modulation, with mGlu5 inhibition or mGlu4 stimulation potentially treating conditions like chronic pain and Parkinson's disease. As an allosteric modulator that can bind both receptors, 2-Methyl-6-(phenylethynyl)pyridine (MPEP) is able to negatively modulate mGlu5 or positively modulate mGlu4. At a structural level, how it elicits these responses and how mGluRs undergo activation is unclear...
July 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28692652/developmental-transcriptomic-analyses-for-mechanistic-insights-into-critical-pathways-involved-in-embryogenesis-of-pelagic-mahi-mahi-coryphaena-hippurus
#12
Elvis Genbo Xu, Edward M Mager, Martin Grosell, John D Stieglitz, E Starr Hazard, Gary Hardiman, Daniel Schlenk
Mahi-mahi (Coryphaena hippurus) is a commercially and ecologically important species of fish occurring in tropical and temperate waters worldwide. Understanding early life events is crucial for predicting effects of environmental stress, which is largely restricted by a lack of genetic resources regarding expression of early developmental genes and regulation of pathways. The need for anchoring developmental stages to transcriptional activities is highlighted by increasing evidence on the impacts of recurrent worldwide oil spills in this sensitive species during early development...
2017: PloS One
https://www.readbyqxmd.com/read/28683325/silent-allosteric-modulation-of-mglur5-maintains-glutamate-signaling-while-rescuing-alzheimer-s-mouse-phenotypes
#13
Laura T Haas, Santiago V Salazar, Levi M Smith, Helen R Zhao, Timothy O Cox, Charlotte S Herber, Andrew P Degnan, Anand Balakrishnan, John E Macor, Charles F Albright, Stephen M Strittmatter
Metabotropic glutamate receptor 5 (mGluR5) has been implicated in Alzheimer's disease (AD) pathology. We sought to understand whether mGluR5's role in AD requires glutamate signaling. We used a potent mGluR5 silent allosteric modulator (SAM, BMS-984923) to separate its well-known physiological role in glutamate signaling from a pathological role in mediating amyloid-β oligomer (Aβo) action. Binding of the SAM to mGluR5 does not change glutamate signaling but strongly reduces mGluR5 interaction with cellular prion protein (PrP(C)) bound to Aβo...
July 5, 2017: Cell Reports
https://www.readbyqxmd.com/read/28679049/role-of-mglu5-receptors-and-inhibitory-neurotransmission-in-m1-dependent-muscarinic-ltd-in-the-prefrontal-cortex-implications-in-schizophrenia
#14
Ayan Ghoshal, Sean P Moran, Jonathan W Dickerson, Max E Joffe, Brad A Grueter, Zixiu Xiang, Craig W Lindsley, Jerri M Rook, P Jeffrey Conn
Selective potentiation of the mGlu5 subtype of metabotropic glutamate (mGlu) receptor using positive allosteric modulators (PAMs) has robust cognition-enhancing effects in rodent models that are relevant for schizophrenia. Until recently, these effects were thought to be due to potentiation of mGlu5-induced modulation of NMDA receptor (NMDAR) currents and NMDAR-dependent synaptic plasticity. However, "biased" mGlu5 PAMs that do not potentiate mGlu5 effects on NMDAR currents show efficacy that is similar to that of prototypical mGlu5 PAMs, suggesting that NMDAR-independent mechanisms must be involved in these actions...
July 5, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28673833/the-glutamate-receptor-antagonists-cnqx-and-mpep-decrease-fast-ripple-events-in-rats-treated-with-kainic-acid
#15
Laura Medina-Ceja, Carla García-Barba
Fast ripples (FR) are high frequency oscillations (250-600Hz) that have been associated with epilepsy. FR are assumed to be generated in small areas of the hippocampus (1mm(3)) that contain pathologically interconnected glutamate pyramidal cell clusters. Additionally, a relation between glutamate neurotransmission and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainite (AMPA/KA) and metabotropic mGluR5 receptors is well established. Therefore, we hypothesized that antagonism of these glutamate receptors would decrease FR activity...
June 30, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28669525/mechanisms-of-skin-toxicity-associated-with-metabotropic-glutamate-receptor-5-negative-allosteric-modulators
#16
Falgun Shah, Antonia F Stepan, Alison O'Mahony, Sharlene Velichko, Alexandra E Folias, Christopher Houle, Christopher L Shaffer, John Marcek, Jessica Whritenour, Robert Stanton, Ellen L Berg
Cutaneous reactions represent one of the most common adverse drug effects observed in clinical trials leading to substantial compound attrition. Three negative allosteric modulators (NAMs) of metabotropic glutamate receptors (mGluRs), which represent an important target for neurological diseases, developed by Pfizer, were recently failed in preclinical development due to delayed type IV skin hypersensitivity observed in non-human primates (NHPs). Here we employed large-scale phenotypic profiling in standardized panels of human primary cell/co-culture systems to characterize the skin toxicity mechanism(s) of mGluR5 NAMs from two different series...
July 20, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28664928/co-activation-of-metabotropic-glutamate-receptor-3-and-beta-adrenergic-receptors-modulates-cyclic-amp-long-term-potentiation-and-disrupts-memory-reconsolidation
#17
Adam G Walker, Douglas J Sheffler, Andrew S Lewis, Jonathan W Dickerson, Daniel J Foster, Rebecca K Senter, Mark S Moehle, Xiaohui Lv, Branden J Stansley, Zixiu Xiang, Jerri M Rook, Kyle A Emmitte, Craig W Lindsley, P Jeffrey Conn
Activation of β-adrenergic receptors (βARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with βARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A1 adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal βARs on excitatory transmission...
June 30, 2017: Neuropsychopharmacology: Official Publication of the American College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28661401/pharmacological-evidence-for-a-metabotropic-glutamate-receptor-heterodimer-in-neuronal-cells
#18
David Moreno Delgado, Thor C Møller, Jeanne Ster, Jesús Giraldo, Damien Maurel, Xavier Rovira, Pauline Scholler, Jurrian M Zwier, Julie Perroy, Thierry Durroux, Eric Trinquet, Laurent Prezeau, Philippe Rondard, Jean-Philippe Pin
Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, sixteen possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here we set up two assays to specifically identify the pharmacological properties of rat mGlu heterodimers composed of mGlu2 and 4 subunits. We used either a heterodimer specific conformational LRET-based biosensor, or a system that guarantees the cell surface targeting of the heterodimer only...
June 29, 2017: ELife
https://www.readbyqxmd.com/read/28655286/a-group-ii-metabotropic-glutamate-receptor-3-mglu3-grm3-isoform-implicated-in-schizophrenia-interacts-with-canonical-mglu3-and-reduces-ligand-binding
#19
Aintzane García-Bea, Isabel Bermudez, Paul J Harrison, Tracy A Lane
As well as being expressed as a full-length transcript, the group II metabotropic glutamate receptor 3 (GRM3, mGlu3) gene is expressed as an mRNA isoform which lacks exon 4 (GRM3Δ4) and which is predicted to encode a protein with a novel C terminus (called mGlu3Δ4). This variant may contribute to the mechanism by which GRM3 acts as a schizophrenia risk gene. However, little is known about the properties or function of mGlu3Δ4. Here, using transiently transfected HEK293T/17 cells, we confirm that GRM3Δ4 cDNA is translated, with mGlu3Δ4 existing as a homodimer as well as a monomer, and localizing primarily to cell membranes including the plasma membrane...
June 1, 2017: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/28648611/molecular-switches-of-allosteric-modulation-of-the-metabotropic-glutamate-2-receptor
#20
Laura Pérez-Benito, Maarten L J Doornbos, Arnau Cordomí, Luc Peeters, Hilde Lavreysen, Leonardo Pardo, Gary Tresadern
Metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) crucial for CNS function and important drug discovery targets. Glutamate triggers receptor activation from an extracellular domain binding site while allosteric modulators bind in the seven-transmembrane domain. Little is known about how allosteric modulators produce their functional effects at the molecular level. Here we address this topic with combined experimental and computational approaches and reveal that mGlu receptor allosteric modulators interact with the homologous "trigger switch" and "transmission switch" amino acids as seen in class A GPCRs, in short, the characteristic hallmarks of class A agonist activation translate to the mGlu allosteric modulator...
July 5, 2017: Structure
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