Association of Long-Term Nicotine Abstinence With Normal Metabotropic Glutamate Receptor-5 Binding
Funda AkkusValérie TreyerAnass JohayemSimon M. AmetameyBaltazar Gomez MancillaJudit SóvágóAlfred BuckGregor Hasler
36
Citation
36
Reference
10
Related Paper
Citation Trend
Cite
Citations (68)
The group 1 metabotropic glutamate receptor, mGluR5, is found on the cell surface as well as on intracellular membranes where it can mediate both overlapping and unique signaling effects. Previously we have shown that glutamate activates intracellular mGluR5 by entry through sodium-dependent transporters and/or cystine glutamate exchangers. Calibrated antibody labelling suggests that the glutamate concentration within neurons is quite high (~10 mM) raising the question as to whether intracellular mGluR5 is maximally activated at all times or whether a different ligand might be responsible for receptor activation. To address this issue, we used cellular, optical and molecular techniques to show that intracellular glutamate is largely sequestered in mitochondria; that the glutamate concentration necessary to activate intracellular mGluR5 is about ten-fold higher than what is necessary to activate cell surface mGluR5; and uncaging caged glutamate within neurons can directly activate the receptor. Thus these studies further the concept that glutamate itself serves as the ligand for intracellular mGluR5.
Cite
Citations (17)
Fragile X Syndrome
Cite
Citations (73)
The metabotropic glutamate receptors (mGluRs) are a family of G‐protein linked receptors that can be divided into three groups (group I, II and III). A number of studies have implicated group I mGluR activation in acute neuronal injury, but until recently it was not possible to pharmacologically differentiate the roles of the two individual subunits (mGluR1 and mGluR5) in this group. We investigated the role of mGluR5 in acute NMDA and glutamate mediated neurodegeneration in cultured rat cortical cells using the mGluR5 antagonists MPEP and SIB‐1893, and found that they provide significant protection at concentrations of 20 or 200 μ M . These compounds act as effective mGluR5 antagonists in our cell culture system, as indicated by the ability of SIB‐1893 to prevent phosphoinositol hydrolysis induced by the specific mGluR5 agonist, (RS)‐2‐chloro‐5‐hydroxyphenylglycine (CHPG). However, they also significantly reduce NMDA evoked current recorded from whole cells voltage clamped at −60 mV, and significantly decrease the duration of opening of NMDA channels recorded in the outside out patch configuration. This suggests that although MPEP and SIB‐1893 are effective mGluR5 antagonists, they also act as noncompetitive NMDA receptor antagonists. Therefore, the neuroprotective effects of these compounds are most likely mediated through their NMDA receptor antagonist action, and caution should be exercised when drawing conclusions about the roles of mGluR5 based on their use. British Journal of Pharmacology (2000) 131 , 1429–1437; doi: 10.1038/sj.bjp.0703715
Cite
Citations (194)
FMR1
Fragile X Syndrome
Knockout mouse
Cite
Citations (96)
Synaptic plasticity is thought to be a key mechanism of information storage in the CNS. Different forms of synaptic long-term potentiation have been shown to be impaired in neurological disorders. Here, we show that metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), but not NMDA receptor-dependent LTD at Schaffer collateral–CA1 synapses, is profoundly impaired after status epilepticus. Brief application of the group I mGluR agonist ( R , S )-3,5-dihydroxyphenylglycine (100 μ m ; 5 min) induced mGluR LTD in control, but not in pilocarpine-treated rats. Experiments in the presence of selective inhibitors of either mGluR5 [2-methyl-6-(phenylethynyl)-pyridine] or mGluR1 [7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and ( S )-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid] demonstrate that loss of mGluR LTD is most likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcription PCR revealed a specific downregulation of mGluR5 mRNA, but not of mGluR1 mRNA in the CA1 region. Furthermore, we detected a strong reduction in mGluR5 protein expression by immunofluorescence and quantitative immunoblotting. Additionally, the scaffolding protein Homer that mediates coupling of mGluR5 to downstream signaling cascades was downregulated. Thus, we conclude that the reduction of mGluR LTD after pilocarpine-induced status epilepticus is the result of the subtype-specific downregulation of mGluR5 and associated downstream signaling components.
Long-term depression
Depression
Cite
Citations (59)
1-Aminocyclopentane-trans-1,3-dicarboxylic acid, an agonist of the metabotropic glutamate receptors 1, 2, 3 and 5, prevents neurotoxicity of glutamate and of N-methyl-D-aspartate in primary cultures of cerebellar neurons. The aim of this work was to assess which of the metabotropic glutamate receptors (mGluRs) is responsible for the protective effect. We tested the protective effects of selective agonists for each type of receptor. It is shown that glutamate and N-methyl-D-aspartate neurotoxicity are prevented by the following compounds: 1-amino-cyclo-pentane-trans-1,3-dicarboxylic acid, agonist of mGluR1, 2, 3 and 5; 3,5-dihydroxyphenylglycine, agonist of mGluR1 and 5; S-4-carboxy-3-hydroxyphenylglycine, agonist of mGluR5 and antagonist of mGluR1; trans-azetidine-2,4-dicarboxylic acid, agonist of mGluR5. Glutamate neurotoxicity is not prevented by (2S,1'S,2'S)-2(2'-carboxycyclopropyl)glycine, an agonist of mGluR2 and mGluR3. Moreover, the protective effect of 1-aminocyclo-pentane-trans-1,3-dicarboxylic acid is prevented by alpha-methyl-4-carboxyphenylglycine, an antagonist of mGluR1 and 5, but not by alpha-methyl-4-tetrazoylphenylglycine, an antagonist of mGluR2 and 3. A protective effect of activation of mGluR1 can not be ruled out because of the limitations imposed by the lack of specificity of the agonists and antagonists currently available. The results shown clearly indicate that activation of mGluR5 prevents glutamate and N-methyl-D-aspartate neurotoxicity in primary cultures of cerebellar neurons.
Cite
Citations (28)
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. Prion-mimetic antibodies increased mGluR5 clustering around dendritic spines, mimicking the toxicity of Aβ oligomers. Oral treatment with the mGluR5 inhibitor, MPEP, delayed the onset of motor deficits and moderately prolonged survival of prion-infected mice. Although group-I mGluR inhibition was not curative, these results suggest that it may alleviate the neurological dysfunctions induced by prion diseases.
Neurotoxicity
Cite
Citations (46)
Metabotropic glutamate receptors (mGluRs) are G-protein-coupled receptors that modulate excitatory neurotransmission and synaptic plasticity. The group I mGluRs (mGluR1 and mGluR5) have long intracellular C-terminal domains, which interact with many proteins. Our previous studies identified calmodulin (CaM) as a strong regulator of mGluR5 trafficking and mGluR5-induced calcium signaling. Although it has been accepted that both mGluR1 and mGluR5 interact with CaM, we now show that CaM specifically binds mGluR5 and not mGluR1. We have identified a single critical residue in mGluR5 (L896) that is required for CaM binding. In mGluR1, mutation of the corresponding residue, V909, to leucine is sufficient to confer CaM binding to mGluR1. To investigate the functional effects of CaM binding, we examined the surface expression of mGluR1 and mGluR5 in hippocampal neurons. The mutation in mGluR1 (V909L) that confers CaM binding dramatically increases mGluR1 surface expression, whereas the analogous mutation in mGluR5 that disrupts CaM binding (L896V) decreases mGluR5 surface expression. In addition, the critical residue that alters CaM binding regulates mGluR internalization. Furthermore, we find that mGluR-mediated AMPA receptor endocytosis is enhanced by CaM binding to group I mGluRs. Finally, we show that calcium responses evoked by group I mGluRs are modulated by these mutations, which regulate CaM binding. Our findings elucidate a critical mechanism that specifically affects mGluR5 trafficking and signaling, and distinguishes mGluR1 and mGluR5 regulation.
Cite
Citations (46)
Astrocytes regulate and respond to extracellular glutamate levels in the central nervous system (CNS) via the Na+-dependent glutamate transporters glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST) and the metabotropic glutamate receptors (mGluR) 3 and mGluR5. Both impaired astrocytic glutamate clearance and changes in metabotropic glutamate signaling could contribute to the development of epilepsy. Dysregulation of astrocytic glutamate transporters, GLT-1 and GLAST, is a common finding across patients and preclinical seizure models. Astrocytic metabotropic glutamate receptors, particularly mGluR5, have been shown to be dysregulated in both humans and animal models of temporal lobe epilepsy (TLE). In this review, we synthesize the available evidence regarding astrocytic glutamate homeostasis and astrocytic mGluRs in the development of epilepsy. Modulation of astrocyte glutamate uptake and/or mGluR activation could lead to novel glial therapeutics for epilepsy.
Glutamate aspartate transporter
Cite
Citations (48)