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Metabotropic glutamate receptor

John J Marshall, Jian Xu, Anis Contractor
Kainate receptors are members of the glutamate receptor family that function both by generating ionotropic currents through an integral ion channel pore, and through coupling to downstream metabotropic signaling pathways. They are highly expressed in the striatum yet their roles in regulating striatal synapses are not known. Using mice of both sexes we demonstrate that GluK2 containing kainate receptors expressed in direct pathway Spiny Projection Neurons (dSPNs) inhibit glutamate release at corticostriatal synapses in the dorsolateral striatum...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Juan R Martinez-Galan, Ana Verdejo, Elena Caminos
Disturbances in calcium homeostasis due to canonical transient receptor potential (TRPC) and/or store-operated calcium (SOC) channels can play a key role in a large number of brain disorders. TRPC channels are plasma membrane cation channels included in the transient receptor potential (TRP) superfamily. The most widely distributed member of the TRPC subfamily in the brain is TRPC1, which is frequently linked to group I metabotropic glutamate receptors (mGluRs) and to the components of SOC channels. Proposing TRPC/SOC channels as a therapeutic target in neurological diseases previously requires a detailed knowledge of the distribution of such molecules in the brain...
2018: Frontiers in Neuroanatomy
Kenneth J O'Riordan, Neng-Wei Hu, Michael J Rowan
Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor...
March 13, 2018: Scientific Reports
Chady Nasrallah, Karine Rottier, Romain Marcellin, Vincent Compan, Joan Font, Amadeu Llebaria, Jean-Philippe Pin, Jean-Louis Banères, Guillaume Lebon
The metabotropic glutamate (mGlu) receptors are class C G protein-coupled receptors (GPCRs) that modulate synaptic activity and plasticity throughout the mammalian brain. Signal transduction is initiated by glutamate binding to the venus flytrap domains (VFT), which initiates a conformational change that is transmitted to the conserved heptahelical domains (7TM) and results ultimately in the activation of intracellular G proteins. While both mGlu1 and mGlu5 activate Gαq G-proteins, they also increase intracellular cAMP concentration through an unknown mechanism...
March 13, 2018: Scientific Reports
Giuseppe Battaglia, Valeria Bruno
Amyotrophic lateral sclerosis (ALS) is a complex genetic, late age-onset, progressive neurodegenerative disorder leading to the death of upper and lower motor neurons. Life expectancy after diagnosis is short due to the ongoing degeneration and to the lack of effective treatments. Axonal alterations, mitochondrial deficits, RNA changes, protein misfolding and turnover, glial dysfunction and hyperexcitability are key players in molecular mechanisms involved in the degeneration of motor neurons. In the context of hyperexcitability, metabotropic glutamate (mGlu) receptors, which are widely distributed throughout the central nervous system and act through many intracellular signaling pathways, are emerging as novel potential drug targets for the therapeutic treatment of ALS, as they are able to counteract excitotoxicity by reducing glutamate release and inducing the production of neurotrophic factors...
March 9, 2018: Current Opinion in Pharmacology
Paula Pierozan, Marie Andersson, Ingvar Brandt, Oskar Karlsson
The environmental neurotoxin β-N-methylamino-L-alanine (BMAA) is a glutamate receptor agonist that can induce oxidative stress and has been implicated as a possible risk factor for neurodegenerative disease. Detection of BMAA in mussels, crustaceans and fish, illustrates that the sources of human exposure to this toxin are more abundant than previously anticipated. The aim of this study was to determine uptake of BMAA in the pineal gland and subsequent effects on melatonin production in primary pinealocyte cultures and a rat model...
March 12, 2018: Journal of Pineal Research
Luisa Iacovelli, Rosamaria Orlando, Alessandro Rossi, Paola Spinsanti, Daniela Melchiorri, Ferdinando Nicoletti
In spite of the recent advancement in the molecular characterization of malignant gliomas and medulloblastomas, the treatment of primary brain tumors remains suboptimal. The use of small molecule inhibitors of intracellular signaling pathways, inhibitors of angiogenesis, and immunotherapic agents is limited by systemic adverse effects, limited brain penetration, and, in some cases, lack of efficacy. Thus, adjuvant chemo-therapy and radiotherapy still remain the gold standard in the treatment of grade-IV astrocytoma (glioblastoma multiforme) and medulloblastoma...
March 8, 2018: Current Opinion in Pharmacology
Hirokazu Hirai, Masanobu Kano
Neurodegenerative diseases such as spinocerebellar ataxias and autoantibody-associated disorders of the central nervous system often affect the cerebellum, resulting in motor deficits. Recent studies have revealed that most of these disorders impair type 1 metabotropic glutamate receptor (mGluR1) and/or the closely associated signaling molecules in cerebellar Purkinje cell. Since the signaling pathway triggered by mGluR1 activation in Purkinje cell plays a pivotal role in coordinated movements and motor learning, pharmacological repair of aberrant mGluR1 signaling in Purkinje cell is critical for mitigation of cerebellar symptoms...
March 8, 2018: Current Opinion in Pharmacology
Ishan Gupta, Andrew M J Young
The non-competitive glutamate antagonist, phencyclidine is used in rodents to model behavioural deficits see in schizophrenia. Importantly, these deficits endure long after the cessation of short-term chronic treatment (sub-chronic), indicating that the drug treatment causes long-term changes in the physiology and/or chemistry of the brain. There is evidence that this may occur through glutamatergic modulation of mesolimbic dopamine release, perhaps involving metabotropic glutamate receptors (mGluR). This study sought to investigate the effect of sub-chronic phencyclidine pretreatment on modulation of dopamine neurotransmission by metabotropic glutamate receptors 2 and 5 (mGluR2 and mGluR5) in the nucleus accumbens shell in vitro, with the hypothesis that phencyclidine pretreatment would disrupt the mGluR-mediated modulation of dopamine release...
March 7, 2018: Brain Research
Tingting Fu, Guoxun Zheng, Gao Tu, Fengyuan Yang, Yu Zong Chen, Xiaojun Yao, Xiaofeng Li, Weiwei Xue, Feng Zhu
Metabotropic glutamate receptor 5 (mGlu5) plays a key role in synaptic information storage and memory, which is a well-known target for a variety of psychiatric and neurodegenerative disorders. In recent years, the increasing efforts have been focused on the design of allosteric modulators, and the negative allosteric modulators (NAMs) are the front runners. Recently, the architecture of transmembrane (TM) domain of mGlu5 receptor has been determined by crystallographic experiment. However, it has been not well understood how the pharmacophores of NAMs accommodated into the allosteric binding site...
March 9, 2018: ACS Chemical Neuroscience
Agostinho Lemos, Rita Meloc, Antonio J Preto, Jose G Almeida, Irina S Moreira, M Natalia D S Cordeiro
Parkinson's Disease (PD) is a long-term neurodegenative brain disorder that mainly affects the motor system. The causes are still unknown, and even though currently there is no cure, several therapeutic options are available to manage its symptoms. The development of novel anti-parkinsonian agents and an understanding of their proper and optimal use are, indeed, highly demanding. For the last decades, L-3,4-DihydrOxyPhenylAlanine or levodopa (L-DOPA) has been the gold-standard therapy for the symptomatic treatment of motor dysfunctions associated to PD...
March 8, 2018: Current Neuropharmacology
Panos Zanos, Scott M Thompson, Ronald S Duman, Carlos A Zarate, Todd D Gould
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, anti-suicidal, and anti-anhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-D-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites...
March 7, 2018: CNS Drugs
Mehdi Borjkhani, Fariba Bahrami, Mahyar Janahmadi
According to a broad range of research, opioids consumption can lead to pathological memory formation. Experimental observations suggested that hippocampal glutamatergic synapses play an indispensable role in forming such a pathological memory. It has been suggested that memory formation at the synaptic level is developed through LTP induction. Here, we attempt to computationally indicate how morphine induces pathological LTP at hippocampal CA3-CA1 synapses. Then, based on simulations, we will suggest how one can prevent this type of pathological LTP...
2018: PloS One
Ida Marabese, Serena Boccella, Monica Iannotta, Livio Luongo, Vito de Novellis, Francesca Guida, Nicola Serra, Antonio Farina, Sabatino Maione, Enza Palazzo
The study investigated the role of the metabotropic glutamate receptor subtype 7 (mGluR7) in pain signalling in the dorsal striatum of sham and neuropathic rats. Supraspinal circuitries involved in the dorsal striatum control of pain were also explored. In the sham rats, microinjection of N,N'-bis(diphenylmethyl)-1,2-ethanediamine (AMN082), a selective mGluR7 positive allosteric modulator, into the dorsal striatum, facilitated pain, increased the activity of the ON cells and inhibited the activity of the OFF cells in the rostral ventromedial medulla, and decreased glutamate levels in the dorsal striatum...
March 2, 2018: Neuropharmacology
Katherine R Tonn Eisinger, Kellie S Gross, Brian P Head, Paul G Mermelstein
Estrogen receptors α and β (ERα and ERβ) have a unique relationship with metabotropic glutamate receptors (mGluRs) in the female rodent brain such that estradiol is able to recruit intracellular G-protein signaling cascades to influence neuronal physiology, structure, and ultimately behavior. While this association between ERs and mGluRs exists in many cell types and brain regions, its effects are perhaps most striking in the nucleus accumbens (NAc). This review will discuss the original characterization of ER/mGluR signaling and how estradiol activity in the NAc confers increased sensitivity to drugs of abuse in females through this mechanism...
March 2, 2018: Hormones and Behavior
György Szabó, György István Túrós, Sándor Kolok, Mónika Vastag, Zsuzsanna Sánta, Miklós Dékány, György I Lévay, István Greiner, Minami Natsumi, Watanabe Tatsuya, Gyorgy M Keseru
Metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs) have been implicated as potential pharmacotherapy for psychiatric conditions. Screening our corporate compound deck, we identified a benzotriazole fragment (4) that was rapidly optimized to a potent and metabolically stable early lead (16). The highly lipophilic character of 16, together with its limited solubility, permeability and high protein binding, however, did not allow to reach the proof of concept in vivo. Since further attempts on the optimization of druglike properties were unsuccessful, the original hit 4 has been revisited and was optimized following the principles of fragment based drug discovery (FBDD)...
March 5, 2018: Journal of Medicinal Chemistry
Ya-Bo Feng, You-Ting Lin, Yu-Xiang Han, Yue-Jiu Pang, Jing-Jing Xu, Yuan Xue, Hong Yao
This study aimed to study the protective effect of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), a selective metabotropic glutamate receptor agonist, against hippocampal neuronal apoptosis induced by seizures in a rat model of pilocarpine-induced epilepsy. The Morris water maze test was used to assess the spatial memory abilities of epileptic rats with or without 2R,4R-APDC treatment. TUNEL assay was performed to examine neuronal apoptosis in hippocampus. Western blot was conducted to evaluate changes in the levels of caspase-3 and caspase-9 in hippocampus...
March 1, 2018: Neurochemical Research
Leniz F Nurullin, Evgeny E Nikolsky, Artem I Malomouzh
It is generally accepted that gamma-aminobutyric acid (GABA) is a signaling molecule abundant in central synapses. In a number of studies though, it has been shown that GABA signaling functions in the peripheral nervous system as well, in particular, in the synapses of sympathetic ganglia. However, there exists no firm evidence on the presence of GABAergic signaling cascade in the intercellular junctions of the somatic nerve system. By the use of immunohistochemistry methods, in the synaptic area of cholinergic neuromuscular contact in rat diaphragm, we have detected glutamate decarboxylase, the enzyme involved in synthesis of GABA, molecules of GABA, and also GAT-2, a protein responsible for transmembrane transport of GABA...
February 26, 2018: Acta Histochemica
Francesco Ferraguti
Anxiety disorders are highly prevalent psychiatric illnesses posing an important social and economic burden. Their current pharmacotherapy shows short term efficacy, though nearly one third of patients do not achieve sustained remission. There is, therefore, a strong medical need for new therapeutic agents acting through novel mechanisms of action. Considerable work has focused on metabotropic glutamate (mGlu) receptors as potential targets for novel anxiolytics. Ligands acting at mGlu receptors showed promising results in preclinical studies, whereas their efficacy was dubious in clinical trials...
February 26, 2018: Current Opinion in Pharmacology
Maarten L J Doornbos, Xuesong Wang, Sophie C Vermond, Luc Peeters, Laura Pérez-Benito, Andrés A Trabanco, Hilde Lavreysen, José María Cid, Laura H Heitman, Gary Tresadern, Adriaan P IJzerman
Covalent labelling of G protein-coupled receptors (GPCRs) by small molecules is a powerful approach to understand binding modes, mechanism of action, pharmacology and even facilitate structure elucidation. We report the first covalent positive allosteric modulator (PAM) for a class C GPCR, the mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modelling combined with receptor mutagenesis revealed T7917...
March 1, 2018: Journal of Medicinal Chemistry
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