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https://www.readbyqxmd.com/read/29455105/shedding-light-on-metabotropic-glutamate-receptors-using-optogenetics-and-photopharmacology
#1
REVIEW
Cyril Goudet, Xavier Rovira, Amadeu Llebaria
Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors activated by glutamate, the main excitatory neurotransmitter of the mammalian central nervous system. These receptors are considered as potential therapeutic targets in many neurological diseases but a better understanding of their complex molecular dynamics and of their role in the normal and pathological functioning of the brain is still required. Manipulating mGluRs with high spatial and temporal precision holds great promise for deciphering their physiological and pathological functions...
February 15, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29421611/gpr30-activation-improves-memory-and-facilitates-dhpg-induced-ltd-in-the-hippocampal-ca3-of-middle-aged-mice
#2
Wen Xu, Jian Cao, Yan Zhou, Lina Wang, Guoqi Zhu
Reduced estrogen levels and decreased expression of related receptors are typical cerebral features of aging. The G protein-coupled estrogen receptor 1 (GPER1, also known as GPR30) is considered a novel therapeutic target for neurodegenerative diseases. In this study, we demonstrated that hippocampal GPR30 expression was reduced in middle-aged mice compared with young adult mice. GPR30 agonist G1 improved both fear and spatial memory in both male and female middle-aged mice, but not in young adult mice, which were blocked by the GPR30 antagonist G15...
February 5, 2018: Neurobiology of Learning and Memory
https://www.readbyqxmd.com/read/29407217/the-role-of-19s-proteasome-associated-deubiquitinases-in-activity-dependent-hippocampal-synaptic-plasticity
#3
Di Yun, Yinghan Zhuang, Michael R Kreutz, Thomas Behnisch
Posttranslational modification and degradation of proteins by the ubiquitin-proteasome system (UPS) is crucial to synaptic transmission. It is well established that 19S proteasome associated deubiquitinases (DUBs) reverse the process of ubiquitination by removing ubiquitin from their substrates. However, their potential contribution to hippocampal synaptic plasticity has not been addressed in detail. Here, we report that inhibition of the 19S proteasome associated DUBs, ubiquitin C-terminal hydrolase 5 (UCHL5) and ubiquitin-specific peptidase 14 (USP14) by b-AP15 results in an accumulation of polyubiquitinated proteins and a reduction of monomeric ubiquitin without overt effects on 26S proteasome activity...
January 30, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29387966/glutamatergic-mechanisms-in-l-dopa-induced-dyskinesia-and-therapeutic-implications
#4
Manuela Mellone, Fabrizio Gardoni
Overactivation of the glutamatergic synapse leading to maladaptive synaptic plasticity in the basal ganglia is a well-demonstrated process involved in the onset of L-DOPA-induced dyskinesia (LID). Changes in glutamate release are paralleled by compensatory modifications of the expression and/or synaptic localization of both ionotropic and metabotropic glutamate receptors (mGluRs). Accordingly, compounds targeting N-methyl-D-aspartate glutamate receptors (NMDARs) and specific subtypes of metabotropic glutamate receptors (mGluR4 and mGluR5) have been tested both in preclinical and clinical studies...
January 31, 2018: Journal of Neural Transmission
https://www.readbyqxmd.com/read/29377390/metabotropic-glutamate-receptor-subtype-7-has-critical-roles-in-regulation-of-the-endocrine-system-and-social-behaviors
#5
Miwako Masugi-Tokita, Tetsuya Yoshida, Susumu Kageyama, Mitsuhiro Kawata, Akihiro Kawauchi
Metabotropic glutamate receptor subtype 7 (mGluR7) is one of the group III mGluRs, which are negatively coupled to adenylate cyclase via Gi/Go proteins and localized to presynaptic active zones of the mammalian central nervous system. We previously reported that mGluR7 is essential for intermale aggression and amygdala-dependent fear learning. To elucidate the role of mGluR7 in the neuroendocrine system, we performed biochemical analyses and found a significant reduction of testosterone levels in mGluR7 knockout (KO) mice...
January 29, 2018: Journal of Neuroendocrinology
https://www.readbyqxmd.com/read/29366625/involvement-of-mglur-i-in-ephb-ephrinb-reverse-signaling-activation-induced-retinal-ganglion-cell-apoptosis-in-a-rat-chronic-hypertension-model
#6
Yuan Zhao, Qian Li, Xue-Yan Li, Peng Cui, Feng Gao, Ke Zhu, Ling-Zhu Li, Xing-Huai Sun, Zhongfeng Wang
EphB/ephrinB reverse signaling is involved in retinal ganglion cell (RGC) apoptosis in experimental glaucoma. Here, we further investigated the mechanisms underlying EphB/ephrinB reverse signaling activation induced RGC apoptosis in a rat chronic ocular hypertension (COH) model, using patch-clamp techniques in retinal slices. In COH retinas, RGCs showed higher spontaneous firing frequency and much more depolarized membrane potential as compared to control, which was mimicked by intravitreally injection of EphB2-Fc, an activator of ephrinB2...
January 20, 2018: Brain Research
https://www.readbyqxmd.com/read/29363229/acupuncture-inhibition-of-methamphetamine-induced-behaviors-dopamine-release-and-hyperthermia-in-the-nucleus-accumbens-mediation-of-group-ii-mglur
#7
Nam Jun Kim, Yeonhee Ryu, Bong Hyo Lee, Suchan Chang, Yu Fan, Young S Gwak, Chae Ha Yang, Kyle B Bills, Scott C Steffensen, Jin Suk Koo, Eun Young Jang, Hee Young Kim
Methamphetamine (METH) increases metabolic neuronal activity in the mesolimbic dopamine (DA) system and mediates the reinforcing effect. To explore the underlying mechanism of acupuncture intervention in reducing METH-induced behaviors, we investigated the effect of acupuncture on locomotor activity, ultrasonic vocalizations, extracellular DA release in the nucleus accumbens (NAcs) using fast-scan cyclic voltammetry and alterations of brain temperature (an indicator of local brain metabolic activity) produced by METH administration...
January 23, 2018: Addiction Biology
https://www.readbyqxmd.com/read/29360756/selective-blockade-of-the-metabotropic-glutamate-receptor-mglur5-protects-mouse-livers-in-in-vitro-and-ex-vivo-models-of-ischemia-reperfusion-injury
#8
Andrea Ferrigno, Clarissa Berardo, Laura Giuseppina Di Pasqua, Veronica Siciliano, Plinio Richelmi, Ferdinando Nicoletti, Mariapia Vairetti
2-Methyl-6-(phenylethynyl)pyridine (MPEP), a negative allosteric modulator of the metabotropic glutamate receptor (mGluR) 5, protects hepatocytes from ischemic injury. In astrocytes and microglia, MPEP depletes ATP. These findings seem to be self-contradictory, since ATP depletion is a fundamental stressor in ischemia. This study attempted to reconstruct the mechanism of MPEP-mediated ATP depletion and the consequences of ATP depletion on protection against ischemic injury. We compared the effects of MPEP and other mGluR5 negative modulators on ATP concentration when measured in rat hepatocytes and acellular solutions...
January 23, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29339723/fasoracetam-in-adolescents-with-adhd-and-glutamatergic-gene-network-variants-disrupting-mglur-neurotransmitter-signaling
#9
Josephine Elia, Grace Ungal, Charlly Kao, Alexander Ambrosini, Nilsa De Jesus-Rosario, Lene Larsen, Rosetta Chiavacci, Tiancheng Wang, Christine Kurian, Kanani Titchen, Brian Sykes, Sharon Hwang, Bhumi Kumar, Jacqueline Potts, Joshua Davis, Jeffrey Malatack, Emma Slattery, Ganesh Moorthy, Athena Zuppa, Andrew Weller, Enda Byrne, Yun R Li, Walter K Kraft, Hakon Hakonarson
The glutamatergic neurotransmitter system may play an important role in attention-deficit hyperactivity disorder (ADHD). This 5-week, open-label, single-blind, placebo-controlled study reports the safety, pharmacokinetics and responsiveness of the metabotropic glutamate receptor (mGluR) activator fasoracetam (NFC-1), in 30 adolescents, age 12-17 years with ADHD, harboring mutations in mGluR network genes. Mutation status was double-blinded. A single-dose pharmacokinetic profiling from 50-800 mg was followed by a single-blind placebo at week 1 and subsequent symptom-driven dose advancement up to 400 mg BID for 4 weeks...
January 16, 2018: Nature Communications
https://www.readbyqxmd.com/read/29322377/s-ketamine-current-trends-in-emergency-and-intensive-care-medicine
#10
REVIEW
Helmut Trimmel, Raimund Helbok, Thomas Staudinger, Wolfgang Jaksch, Brigitte Messerer, Herbert Schöchl, Rudolf Likar
S(+)-ketamine, the pure dextrorotatory enantiomer of ketamine has been available for clinical use in analgesia and anesthesia for more than 25 years. The main effects are mediated by non-competitive inhibition of the N-methyl-D-aspartate (NMDA) receptor but S(+)-ketamine also interacts with opioid receptors, monoamine receptors, adenosine receptors and other purinergic receptors. Effects on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, metabotropic glutamate receptors (mGluR) and L‑type calcium chanels have also been described...
January 10, 2018: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/29320397/in-silico-analysis-of-the-association-relationship-between-neuroprotection-and-flavors-of-traditional-chinese-medicine-based-on-the-mglurs
#11
Xu Zhang, Liansheng Qiao, Yankun Chen, Bowen Zhao, Yu Gu, Xiaoqian Huo, Yanling Zhang, Gongyu Li
The metabotropic glutamate receptors (mGluRs) are known as both synaptic receptors and taste receptors. This feature is highly similar to the Property and Flavor theory of Traditional Chinese medicine (TCM), which has the pharmacological effect and flavor. In this study, six ligand based pharmacophore (LBP) models, seven homology modeling models, and fourteen molecular docking models of mGluRs were built based on orthosteric and allosteric sites to screening potential compounds from Traditional Chinese Medicine Database (TCMD)...
January 10, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29311141/a-unique-homeostatic-signaling-pathway-links-synaptic-inactivity-to-postsynaptic-mtorc1
#12
Fredrick E Henry, Xiao Wang, David Serrano, Amanda S Perez, Cynthia J L Carruthers, Edward L Stuenkel, Michael A Sutton
mTORC1-dependent translational control plays a key role in several enduring forms of synaptic plasticity such as long term potentiation (LTP) and mGluR-dependent long term depression. Recent evidence demonstrates an additional role in regulating synaptic homeostasis in response to inactivity, where dendritic mTORC1 serves to modulate presynaptic function via retrograde signaling. Presently, it is unclear if LTP and homeostatic plasticity utilize a common route to mTORC1-dependent signaling or if each engage mTORC1 through distinct pathways...
January 8, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29224956/bidirectional-shift-of-group-iii-metabotropic-glutamate-receptor-mediated-synaptic-depression-in-the-epileptic-hippocampus
#13
Fabian Dammann, Timo Kirschstein, Xiati Guli, Steffen Müller, Katrin Porath, Marco Rohde, Tursonjan Tokay, Rüdiger Köhling
A common function of group III metabotropic glutamate receptors (mGluRs) located at the presynaptic site of a glutamatergic synapse is synaptic depression. Here, we studied synaptic depression mediated by group III mGluR activation at Schaffer collateral-CA1 (SC-CA1) synapses and associational-commissural-CA3 (AC-CA3) synapses by recording field excitatory postsynaptic potentials in the in vitro brain slice preparation. In order to gauge the impact of synaptic depression in chronically epileptic tissue, we compared rats after pilocarpine-induced status epilepticus (post-SE) with control animals...
December 7, 2017: Epilepsy Research
https://www.readbyqxmd.com/read/29221855/toll-like-receptor-4-regulates-anxiety-like-behavior-and-darpp-32-phosphorylation
#14
T Femenia, Y Qian, T Arentsen, H Forssberg, R Diaz Heijtz
Toll-like receptors (TLRs) play a crucial role in early innate immune responses to inflammatory agents and pathogens. In the brain, some members of the TLR family are expressed in glial cells and neurons. In particular, TLR4 has been involved in learning and memory processes, stress-induced adaptations, and pathogenesis of neurodegenerative disorders. However, the role of TLR4 in emotional behaviors and their underlying mechanisms are poorly understood. In this study, we investigated the role of TLR4 in emotional and social behavior by using different behavioral approaches, and assessed potential molecular alterations in important brain areas involved in emotional responses...
December 5, 2017: Brain, Behavior, and Immunity
https://www.readbyqxmd.com/read/29220747/effects-of-group-ii-metabotropic-glutamate-receptor-modulation-on-ethanol-and-sucrose-seeking-and-consumption-in-the-rat
#15
Kyle A Windisch, Cristine L Czachowski
Previous studies suggest that group II metabotropic glutamate receptors (mGluR2/3) are involved in regulating ethanol-seeking and consumption. The mGluR2/3 agonist LY379268 (LY37) and selective mGluR2 positive allosteric modulator biphenyl‑indanone A (BINA) were used to investigate the relative contribution of mGlu2 and mGlu3 receptors on ethanol- and sucrose-seeking and consumption. A microinjection study was then performed to examine the role of nucleus accumbens (NAc) core mGluR2/3 on ethanol-seeking. For the systemic experiments, separate groups of male Wistar rats [LY37 (0-2...
September 23, 2017: Alcohol
https://www.readbyqxmd.com/read/29213077/allosteric-nanobodies-uncover-a-role-of-hippocampal-mglu2-receptor-homodimers-in-contextual-fear-consolidation
#16
Pauline Scholler, Damien Nevoltris, Dimitri de Bundel, Simon Bossi, David Moreno-Delgado, Xavier Rovira, Thor C Møller, Driss El Moustaine, Michaël Mathieu, Emilie Blanc, Heather McLean, Elodie Dupuis, Gérard Mathis, Eric Trinquet, Hervé Daniel, Emmanuel Valjent, Daniel Baty, Patrick Chames, Philippe Rondard, Jean-Philippe Pin
Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest in antibody development programs. Metabotropic glutamate receptors are dimeric GPCRs that can control synaptic activity in a multitude of ways. Here we identify llama nanobodies that specifically recognize mGlu2 receptors, among the eight subtypes of mGluR subunits. Among these nanobodies, DN10 and 13 are positive allosteric modulators (PAM) on homodimeric mGlu2, while DN10 displays also a significant partial agonist activity...
December 6, 2017: Nature Communications
https://www.readbyqxmd.com/read/29207276/environmental-enrichment-improves-hippocampal-function-in-aged-rats-by-enhancing-learning-and-memory-ltp-and-mglur5-homer1c-activity
#17
Guiseppe P Cortese, Andrew Olin, Kenneth O'Riordan, Rikki Hullinger, Corinna Burger
Previous studies from our laboratory have shown that environmental enrichment (EE) in young rats results in improved learning ability and enhanced metabotropic glutamate receptor-dependent long-term potentiation (mGluR-dependent LTP) resulting from sustained activation of p70S6 kinase. Here, we investigated whether 1-month EE is sufficient to improve hippocampus-dependent learning and memory and enhance hippocampal LTP in 23-24 month-old Fischer 344 male rats. Aged rats were housed in environmentally enriched, socially enriched, or standard housing conditions...
November 16, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29203851/dynamic-landscape-of-the-local-translation-at-activated-synapses
#18
T M Khlebodarova, V V Kogai, E A Trifonova, V A Likhoshvai
The mammalian target of rapamycin (mTOR) signaling pathway is the central regulator of cap-dependent translation at the synapse. Disturbances in mTOR pathway have been associated with several neurological diseases, such as autism and epilepsy. RNA-binding protein FMRP, a negative regulator of translation initiation, is one of the key components of the local translation system. Activation and inactivation of FMRP occurs via phosphorylation by S6 kinase and dephosphorylation by PP2A phosphatase, respectively...
December 5, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29195167/effects-of-short-and-long-term-aripiprazole-treatment-on-group-i-mglurs-in-the-nucleus-accumbens-comparison-with-haloperidol
#19
Jeremy S Lum, Bo Pan, Chao Deng, Xu-Feng Huang, Lezanne Ooi, Kelly A Newell
The D2 receptor partial agonist, aripiprazole, has shown increased therapeutic efficacy for schizophrenia, autism and Tourette's syndrome compared to traditional antipsychotics such as the D2 receptor antagonist, haloperidol. Recent evidence suggests this superior profile may be associated with downstream effects on glutamatergic synapses. Group 1 metabotropic glutamate receptors (mGluRs) and their endogenous modulators, Norbin and Homer1, are regulated by D2 receptor activity, particularly within the nucleus accumbens (NAc), a target region of aripiprazole and haloperidol...
November 21, 2017: Psychiatry Research
https://www.readbyqxmd.com/read/29176838/inhibition-of-group-i-metabotropic-glutamate-receptors-protects-against-prion-toxicity
#20
Despoina Goniotaki, Asvin K K Lakkaraju, Amulya N Shrivastava, Pamela Bakirci, Silvia Sorce, Assunta Senatore, Rajlakshmi Marpakwar, Simone Hornemann, Fabrizio Gasparini, Antoine Triller, Adriano Aguzzi
Prion infections cause inexorable, progressive neurological dysfunction and neurodegeneration. Expression of the cellular prion protein PrPC is required for toxicity, suggesting the existence of deleterious PrPC-dependent signaling cascades. Because group-I metabotropic glutamate receptors (mGluR1 and mGluR5) can form complexes with the cellular prion protein (PrPC), we investigated the impact of mGluR1 and mGluR5 inhibition on prion toxicity ex vivo and in vivo. We found that pharmacological inhibition of mGluR1 and mGluR5 antagonized dose-dependently the neurotoxicity triggered by prion infection and by prion-mimetic anti-PrPC antibodies in organotypic brain slices...
November 27, 2017: PLoS Pathogens
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