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Metabotropic glutamate receptor

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https://www.readbyqxmd.com/read/28918254/permissive-role-for-mglu1-metabotropic-glutamate-receptors-in-excitotoxic-retinal-degeneration
#1
Francesca Liberatore, Domenico Bucci, Giada Mascio, Michele Madonna, Paola Di Pietro, Martina Beneventano, Alda Maria Puliti, Giuseppe Battaglia, Valeria Bruno, Ferdinando Nicoletti, Maria Rosaria Romano
Neuroprotection is an unmet need in eye disorders characterized by retinal ganglion cell (RGC) death, such as prematurity-induced retinal degeneration, glaucoma, and age- related macular degeneration. In all these disorders excitotoxicity is a prominent component of neuronal damage, but clinical data discourage the development of NMDA receptor antagonists as neuroprotectants. Here, we show that activation of mGlu1 metabotropic glutamate receptors largely contributes to excitotoxic degeneration of RGCs. Mice at postnatal day 9 were challenged with a toxic dose of monosodium glutamate (MSG, 3 g/kg), which caused the death of >70% of Brn-3a(+) RGCs...
September 13, 2017: Neuroscience
https://www.readbyqxmd.com/read/28914419/social-isolation-during-adolescence-induces-anxiety-behaviors-and-enhances-firing-activity-in-bla-pyramidal-neurons-via-mglur5-upregulation
#2
Song Lin, Xin Li, Yi-Hua Chen, Feng Gao, Hao Chen, Neng-Yuan Hu, Lang Huang, Zheng-Yi Luo, Ji-Hong Liu, Qiang-Long You, Ya-Nan Yin, Ze-Lin Li, Xiao-Wen Li, Zhuo-Jun Du, Jian-Ming Yang, Tian-Ming Gao
Social isolation during the vulnerable period of adolescence contributes to the occurrence of psychiatric disorders and profoundly affects brain development and adult behavior. Although the impact of social isolation during adolescence on anxiety behaviors has been well studied, much less is known about the onset and underlying mechanisms of these behaviors. We observed that following 2 weeks, but not 1 week, of social isolation, adolescent mice exhibited anxiety behaviors. Strikingly, the mGluR5 protein levels in the amygdala increased concomitantly with anxiety behaviors, and both intraperitoneal administration and intra-basolateral amygdala (BLA) infusion of MPEP, a metabotropic glutamate receptor 5 antagonist, normalized anxiety behaviors...
September 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28902994/discovery-structure-activity-relationship-and-anti-parkinsonian-effect-of-a-potent-and-brain-penetrant-chemical-series-of-positive-allosteric-modulators-of-metabotropic-glutamate-receptor-4
#3
Delphine Charvin, Vincent Pomel, Millan Ortiz, Mélanie Frauli, Sophie Scheffler, Edith Steinberg, Luc Baron, Laurène Deshons, Rachel Rudigier, Delphine Thiarc, Christophe Morice, Baptiste Manteau, Stanislas Mayer, Danielle Graham, Bruno Giethlen, Nadia Brugger, Gaël Hedou, François Conquet, Stephan Schann
The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinson's disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms, after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model...
September 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28902684/estrogens-synthesized-and-acting-within-a-spinal-oligomer-suppress-spinal-endomorphin-2-antinociception-ebb-and-flow-over-the-rat-reproductive-cycle
#4
Nai-Jiang Liu, Vijaya Murugaiyan, Emiliya M Storman, Stephen A Schnell, Martin W Wessendorf, Alan R Gintzler
The magnitude of antinociception elicited by intrathecal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, varies across the rat estrous cycle. We now report that phasic changes in analgesic responsiveness to spinal EM2 result from plastic interactions within a novel membrane-bound oligomer containing estrogen receptors (mERs), aromatase (aka estrogen synthase), metabotropic glutamate receptor 1 (mGluR1), and MOR. During diestrus, spinal mERs, activated by locally synthesized estrogens, act with mGluR1 to suppress spinal EM2/MOR antinociception...
June 21, 2017: Pain
https://www.readbyqxmd.com/read/28891868/a-bivalent-ligand-that-activates-mu-opioid-receptor-and-antagonizes-mglur5-receptor-reduces-neuropathic-pain-in-mice
#5
Cristina D Peterson, Kelley F Kitto, Eyup Akgün, Mary M Lunzer, Maureen S Riedl, Lucy Vulchanova, George L Wilcox, Philip S Portoghese, Carolyn A Fairbanks
The mu opioid receptor (MOR) and metabotropic glutamate receptor 5 (mGluR5) are well-established pharmacological targets in the management of chronic pain. Both receptors are expressed in spinal cord. MMG22, a bivalent ligand containing two pharmacophores separated by 22 atoms that simultaneously activates MOR and antagonizes mGluR5 has been shown to produce potent reversal of tactile hypersensitivity in rodent models of LPS- and bone-cancer-induced chronic pain. The present study assessed whether intrathecal MMG22 also is effective in reducing pain of neuropathic origin...
September 1, 2017: Pain
https://www.readbyqxmd.com/read/28887860/regulation-of-radial-glial-process-growth-by-glutamate-via-mglur5-trpc3-and-neuregulin-erbb4
#6
Lauri M Louhivuori, Pauli M Turunen, Verna Louhivuori, Venkatram Yellapragada, Tommy Nordström, Per Uhlén, Karl E Åkerman
Radial glial cells play an essential role through their function as guides for neuronal migration during development. Disruption of metabotropic glutamate receptor 5 (mGluR5) function retards the growth of radial glial processes in vitro. Neuregulins (NRG) are activated by proteolytic cleavage and regulate (radial) glial maintenance via ErbB3/ErbB4 receptors. We show here that blocking ErbB4 disrupts radial process extension. Soluble NRG acting on ErbB4 receptors is able to promote radial process extension in particular where process elongation has been impeded by blockade of mGluR5, the nonselective cation channel canonical transient receptor potential 3 (TRPC3), or matrix metalloproteases (MMP)...
September 9, 2017: Glia
https://www.readbyqxmd.com/read/28886343/dominant-mutations-in-grm1-cause-spinocerebellar-ataxia-type-44
#7
Lauren M Watson, Elizabeth Bamber, Ricardo Parolin Schnekenberg, Jonathan Williams, Conceição Bettencourt, Jennifer Lickiss, Katherine Fawcett, Samuel Clokie, Yvonne Wallis, Penny Clouston, David Sims, Henry Houlden, Esther B E Becker, Andrea H Németh
The metabotropic glutamate receptor 1 (mGluR1) is abundantly expressed in the mammalian central nervous system, where it regulates intracellular calcium homeostasis in response to excitatory signaling. Here, we describe heterozygous dominant mutations in GRM1, which encodes mGluR1, that are associated with distinct disease phenotypes: gain-of-function missense mutations, linked in two different families to adult-onset cerebellar ataxia, and a de novo truncation mutation resulting in a dominant-negative effect that is associated with juvenile-onset ataxia and intellectual disability...
September 7, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28884874/cerebral-dopaminergic-and-glutamatergic-transmission-relate-to-different-subjective-responses-of-acute-alcohol-intake-an-in-vivo-multimodal-imaging-study
#8
Gil Leurquin-Sterk, Jenny Ceccarini, Cleo Lina Crunelle, Akila Weerasekera, Bart de Laat, Uwe Himmelreich, Guy Bormans, Koen Van Laere
Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [(18) F]fallypride and [(18) F]FPEB positron emission tomography, respectively...
September 8, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28882644/postsynaptic-n-type-or-p-q-type-calcium-channels-mediate-long-term-potentiation-by-group-i-metabotropic-glutamate-receptors-in-the-trigeminal-oralis
#9
Haein Weon, Tae Wan Kim, Dong-Ho Youn
AIMS: Both N-type and P/Q-type voltage-gated Ca(2+) channels (VGCCs) are involved in the induction of long-term potentiation (LTP), the long-lasting increase of synaptic strength, in the central nervous system. To provide further information on the roles of N-type and P/Q-type VGCCs in the induction of LTP at excitatory synapses of trigeminal primary afferents in the spinal trigeminal subnucleus oralis (Vo), we investigated whether they contribute to the induction of LTP by activation of group I metabotropic glutamate receptors (mGluRs)...
September 4, 2017: Life Sciences
https://www.readbyqxmd.com/read/28880414/levodopa-treatment-and-dendritic-spine-pathology
#10
REVIEW
Haruo Nishijima, Tatsuya Ueno, Yukihisa Funamizu, Shinya Ueno, Masahiko Tomiyama
Parkinson's disease (PD) is a neurodegenerative disorder associated with the progressive loss of nigrostriatal dopaminergic neurons. Levodopa is the most effective treatment for the motor symptoms of PD. However, chronic oral levodopa treatment can lead to various motor and nonmotor complications because of nonphysiological pulsatile dopaminergic stimulation in the brain. Examinations of autopsy cases with PD have revealed a decreased number of dendritic spines of striatal neurons. Animal models of PD have revealed altered density and morphology of dendritic spines of neurons in various brain regions after dopaminergic denervation or dopaminergic denervation plus levodopa treatment, indicating altered synaptic transmission...
September 7, 2017: Movement Disorders: Official Journal of the Movement Disorder Society
https://www.readbyqxmd.com/read/28874824/eif4b-phosphorylation-at-ser504-links-synaptic-activity-with-protein-translation-in-physiology-and-pathology
#11
Barbara Bettegazzi, Serena Bellani, Paolo Roncon, Fabrizia Claudia Guarnieri, Alice Bertero, Franca Codazzi, Flavia Valtorta, Michele Simonato, Fabio Grohovaz, Daniele Zacchetti
Neuronal physiology requires activity-driven protein translation, a process in which translation initiation factors are key players. We focus on eukaryotic initiation factor 4B (eIF4B), a regulator of protein translation, whose function in neurons is undetermined. We show that neuronal activity affects eIF4B phosphorylation and identify Ser504 as a phosphorylation site regulated by casein kinases and sensitive to the activation of metabotropic glutamate receptors. Ser504 phosphorylation increases eIF4B recruitment to the pre-initiation complex and influences eIF4B localization at synapses...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28874540/correction-for-holmes-et-al-altered-metabotropic-glutamate-receptor-5-markers-in-ptsd-in-vivo-and-postmortem-evidence
#12
(no author information available yet)
No abstract text is available yet for this article.
September 5, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28874314/drug-discovery-for-the-treatment-of-substance-use-disorders-novel-targets-repurposing-and-the-need-for-new-paradigms
#13
REVIEW
Cristiano Chiamulera, Laura Padovani, Mauro Corsi
Drug addiction treatment medications available nowadays are limited in both efficacy and number. The increased understanding of drug addiction circuitries leads the scientific community to look for better molecules and targets for detoxification and relapse prevention. This review focus on known targets (e.g., metabotropic glutamate receptor 5 and GABAB receptor) and on novel potential treatment acting on oxytocin system, which interacts with diverse neurotransmitters, has proved successful in both preclinical and clinical studies on ethanol, cocaine and methamphetamine...
September 2, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28870523/antagonism-of-mglu2-3-receptors-in-the-nucleus-accumbens-prevents-oxytocin-from-reducing-cued-methamphetamine-seeking-in-male-and-female-rats
#14
Aurelien Bernheim, Kah-Chung Leong, Carole Berini, Carmela M Reichel
Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin's effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions...
September 1, 2017: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28870203/the-dlgap-family-neuronal-expression-function-and-role-in-brain-disorders
#15
REVIEW
Andreas H Rasmussen, Hanne B Rasmussen, Asli Silahtaroglu
The neurotransmitter glutamate facilitates neuronal signalling at excitatory synapses. Glutamate is released from the presynaptic membrane into the synaptic cleft. Across the synaptic cleft glutamate binds to both ion channels and metabotropic glutamate receptors at the postsynapse, which expedite downstream signalling in the neuron. The postsynaptic density, a highly specialized matrix, which is attached to the postsynaptic membrane, controls this downstream signalling. The postsynaptic density also resets the synapse after each synaptic firing...
September 4, 2017: Molecular Brain
https://www.readbyqxmd.com/read/28864032/in-memory-of-norman-bowery-1944-2016
#16
REVIEW
David G Trist, Terry P Kenakin, Thomas P Blackburn
This article is in memory of Professor Norman Bowery (1944-2016). Norman was a pharmacologist who spent most of his career researching the pharmacology of γ-aminobutyric acid (GABA). He discovered a novel metabotropic receptor subtype, GABAB, that is pharmacologically, and structurally different from the original ionotropic receptor now designated as GABAA. In his research he also studied the neurotransmitters glutamate and substance P, two molecules whose release in parts of the spinal cord is inhibited by baclofen a GABAB receptor agonist...
August 29, 2017: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/28858384/reduced-levels-of-mglu2-receptors-within-the-prelimbic-cortex-not-associated-with-elevated-glutamate-transmission-or-high-alcohol-drinking
#17
Zheng-Ming Ding, Cynthia M Ingraham, Sheketha R Hauser, Amy W Lasek, Richard L Bell, William J McBride
BACKGROUND: A Grm2 cys407* stop codon mutation, which results in a loss of the metabotropic glutamate 2 (mGlu2) receptor protein, was identified as being associated with high alcohol drinking by alcohol preferring (P) rats. The objectives of the current study were to characterize the effects of reduced levels of mGlu2 receptors on glutamate transmission and alcohol drinking. METHODS: Quantitative no-net-flux microdialysis was used to test the hypothesis that basal extracellular glutamate levels in the prelimbic (PL) cortex and nucleus accumbens shell (NACsh) will be higher in P than Wistar rats...
August 31, 2017: Alcoholism, Clinical and Experimental Research
https://www.readbyqxmd.com/read/28855570/metabotropic-glutamate-receptor-5-deficiency-inhibits-neutrophil-infiltration-after-traumatic-brain-injury-in-mice
#18
Ting Yang, Yang-Wuyue Liu, Li Zhao, Hao Wang, Nan Yang, Shuang-Shuang Dai, Fengtian He
Both brain native inflammatory cells and infiltrated peripheral white blood cells (WBCs) are primary participants in the brain inflammatory damage post-TBI. Metabotropic glutamate receptor 5 (mGluR5) has been reported to regulate microglias and astrocytes to affect inflammation after TBI, but its effect on modulating infiltrated peripheral WBCs remains unclear. In a mouse moderate TBI model, we found that mGluR5 knockout (KO) significantly reduced neutrophil infiltration and inflammatory cytokine expression in the brain at 24 hours post TBI, which was accompanied by improved neurological dysfunction...
August 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28851991/upregulation-of-prefrontal-metabotropic-glutamate-receptor-5-mediates-neuropathic-pain-and-negative-mood-symptoms-after-spinal-nerve-injury-in-rats
#19
Geehoon Chung, Chae Young Kim, Yeong-Chan Yun, Sang Ho Yoon, Myoung-Hwan Kim, Yu Kyeong Kim, Sang Jeong Kim
Patients with chronic pain easily accompany the negative mood symptoms such as depression and anxiety, and these disturbances in turn affect the aversive perception of pain. However, the underlying mechanisms are largely unknown. We hypothesized that the alteration of metabotropic glutamate receptor 5 (mGluR5) in the brain region underlies such a comorbidity of aversive states. We scanned the brain of chronic neuropathic pain model rats using positron emission tomography (PET) technique with an mGluR5-selective radiotracer [11C] ABP688 and found various brain regions with higher or lower level of mGluR5 compared to control rats...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28838696/synthesis-and-optimization-of-4-5-6-7-tetrahydrooxazolo-4-5-c-pyridines-as-potent-and-orally-active-metabotropic-glutamate-receptor-5-negative-allosteric-modulators
#20
Wataru Hirose, Yoshihiro Kato, Itaru Natsutani, Makoto Takata, Maiko Kitaichi, Satoki Imai, Shun Hayashi, Yukiyo Arai, Kohei Hoshino, Kohzo Yoshida
We describe here the design, synthesis and characterization of a series of 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridines as metabotropic glutamate receptor (mGluR) 5 negative allosteric modulators (NAMs). Optimization of the substituents led to the identification of several compounds with good pharmacokinetic profiles, including long half life and high oral bioavailability, in both rats and monkeys. The receptor occupancy test in the rat cortex revealed favorable brain penetration of these compounds. The reprsentative compound 13 produced oral antidepressant-like effect in the rat forced swimming test (MED: 0...
September 15, 2017: Bioorganic & Medicinal Chemistry Letters
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