Auswahl der wissenschaftlichen Literatur zum Thema „Récepteurs mGlu“
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Zeitschriftenartikel zum Thema "Récepteurs mGlu"
Berto, Ludovic, Anaëlle Dumazer, Fanny Malhaire, Giuseppe Cannone, Vinothkumar Kutti Ragunath, Cyril Goudet und Guillaume Lebon. „Les avancées récentes dans le domaine de la biologie structurale des récepteurs couplés aux protéines G de la classe C : Le récepteur métabotropique du glutamate 5“. Biologie Aujourd’hui 215, Nr. 3-4 (2021): 85–94. http://dx.doi.org/10.1051/jbio/2021013.
Der volle Inhalt der QuelleDissertationen zum Thema "Récepteurs mGlu"
Scholler, Pauline. „De la compréhension de la dynamique structurale des récepteurs mGlu au développement de nouveaux agents d’intérêt thérapeutique“. Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON13519.
Der volle Inhalt der QuelleGlutamate is the main excitatory neurotransmitter in the central nervous system. It notably acts on eight metabotropic glutamate receptors (mGluR), which are G protein coupled receptor responsible for the modulation of synaptic transmission. mGluRs are promising pharmacological targets to treat neurological, psychiatric or neurodegenerative diseases such as depression, schizophrenia or Parkinson's disease. Unfortunately, so far, no drug acting at mGluR is accessible to patients, but several molecules are in clinical trials. The main objective of my thesis has been the study of the structural dynamics of mGluR, for which the molecular mechanism allowing activation are still poorly understood. These receptors are known to form constitutive dimers, with each subunit composed of a large extracellular domain which bind glutamate and a transmembrane domain responsible for G protein activation and where synthetic allosteric modulators bind. A key step in the activation process could be the relative reorientation of the two extracellular domains in the dimer upon glutamate binding. We first developed an orthogonal labeling method of each mGlu subunits by fusion with a suicide enzyme (SNAP-/CLIP-tag) that we combined with time-resolved Förster resonance energy transfer measurements to show that in a heterologous system, mGlu subunits can associate as strict and functional heterodimers. Our experiments also revealed a specific association pattern: mGlu subunits from group I, mGlu1 and mGlu5, can associate with each other, but not with those from group II and III, which can also associate with each other. Then we improved the technology to develop the first conformational sensor to monitor mGluR activation. We were able to monitor in real time in live cells the conformational changes occurring in the mGlu receptor upon activation, and we proved that the variation in FRET signal is correlated with the activation state of the receptor. This allowed us to confirm the activation model proposed based on the crystal structures of the isolated extracellular domains, which consist of a relative movement of the dimer extracellulair domains upon activation. Moreover, this sensor makes it possible to easily discriminate between full and partial agonists, and to better understand the allosteric mechanisms occurring in the mGluR (especially the action mode of positive and negative allosteric modulators binding in the transmembrane domain). This conformational sensor strategy was further applied to study the activation of other receptors (GPCR or tyrosine kinase receptors), and to develop screening assays compatible with high-throughput formats. Finally, we developed innovative ligands acting on mGluRs using single-domain antibodies from llamas. These activating ligands seem to bind to a new site on the surface of the receptor, offering new possibilities to develop better treatment acting at mGluRs
Pronot, Marie. „Régulation et conséquences fonctionnelles de la SUMOylation à la synapse“. Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://theses.univ-cotedazur.fr/2021COAZ6019.
Der volle Inhalt der QuelleSUMOylation is a dynamic post-translational modification that consists in the covalent but reversible enzymatic conjugation of the Small Ubiquitin-like MOdifier (SUMO) protein on specific lysine residues of target proteins. In the last 10 years, SUMOylation has emerged as an important regulator of the neuronal function, playing a role in brain development, neuronal excitability and synaptic transmission and plasticity. Importantly, alterations in the SUMOylation homeostasis process are associated with a variety of brain disorders. Nevertheless, the regulatory mechanisms remain poorly studied and the available repertoire of identified SUMO substrates at synapses is still extremely limited. The SUMOylation/deSUMOylation balance is orchestrated by the coordinated action of the sole SUMO-conjugating enzyme Ubc9 and SUMO-deconjugating enzymes called SENPs. A tight regulation of this balance is therefore critical to the brain function and its disruption is associated with several neurological disorders. We previously demonstrated that a short activation of mGlu5R transiently traps Ubc9 at the post-synapse, resulting in a rapid increase in the overall synaptic SUMOylation and changes in neuronal excitability. A sustained activation of mGlu5R leads to post-synaptic accumulation of SENP1 and a decrease in synaptic SUMOylation to basal levels. Given that both processes are controlled by the activation of mGlu5R but on a different timescale, other mechanisms must coexist to regulate their spatiotemporal balance at synapses. Using a combination of advanced live-cell imaging, biochemical and pharmacological approaches, we revealed a bidirectional regulation of synaptic deSUMOylation targeting by the group I mGluRs and highlight how PKC and CaMKII activation as well as the polymerization of microtubules drive the neuronal and synaptic redistribution of SENP1. The poor identification of endogenous synaptic SUMOylation substrates is mainly due to the low levels of SUMOylated proteins at synapses but also to the developmental ages investigated. To overcome these difficulties, we combined subcellular fractionation approaches on post-natal (P14) rat brains with specific SUMO2/3 immunoprecipitation to isolate synaptic SUMO2/3-ylated proteins. Then using Orbitrap mass spectrometry (MS), we identified around 800 synaptic SUMO2/3-ylated proteins including the previously reported SUMO targets Ubc9, CASK and Synapsin1. We identified many novel synaptic SUMO targets including PSD95 and SynGAP, further highlighting the central role of SUMOylation in the synaptic function. Interestingly, many of the proteins identified are directly linked to neurological disorders suggesting that the SUMOylation process per se could participate in the aetiology of these brain diseases. Altogether, my PhD work provides additional insights into the sequential activity-dependent regulatory mechanisms driving the homeostasis of protein SUMOylation at the mammalian synapse and establishes the first detailed cartography of synaptic SUMO2/3 substrates
Bossi, Simon. „Récepteurs présynaptiques métabotropiques du glutamate : études fonctionnelles au sein du système nerveux central de rongeur à l'aide de nouveaux outils pharmacologiques“. Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS488.
Der volle Inhalt der QuelleMetabotropic glutamate receptors (mGlus) are known to modulate excitatory transmission in the Central Nervous System. Among them, those situated at the pre-synaptic level behave like autoreceptors, their activation leading to a decrease in glutamate release. Functional studies of the different mGlus have been hampered by the lack of selective pharmacological tools specifically targeting a given subgroup of these receptors. As a first step, using electrophysiological and calcium fluorometry techniques, we validated new specific pharmacological tools acting on mGlu2 (a nanobody, positive allosteric modulator, PAM) and mGlu4 (OptoGluNAM4.1, a negative allosteric modulator, NAM) on rodent hippocampal and cerebellar slices, respectively. We then used the OptoGluNAM4.1 in the cerebellar cortex to demonstrate, for the first time, the involvement of mGlu4 in a physiopathological condition: cerebellar ischemia. Using more conventional pharmacological tools, we were also able to show the existence of a dialog between mGlu4 and A1 (Adenosine type 1) receptors at the level of the synapse between parallel fibers and Purkinje cells. Whether this dialog results from functional interactions between the signaling pathways of these pre-synaptic dimeric receptors and/or is a consequence of their physical association in heterodimers is presently under study
Girard, Benoît. „Impact de l’activation du récepteur mGlu7 dans l’épilepsie“. Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT038.
Der volle Inhalt der QuelleEpilepsy affects millions of patients worldwide. The available treatments are symptomatic, they treat seizures without preventing the progression of the disease and have heavy side effects. The discovery of new therapeutic targets and new compounds is therefore essential to overcome the limitations of current therapeutic strategies. Previous studies have demonstrated substantial involvement of the mGlu7 receptor in modulating not only excitability but also hypersynchronization of neural networks, two crucial factors affecting epileptic seizures. These discoveries were at the origin of a first publication that I completed at the beginning of my thesis (Tassin, Girard et al., 2016).Using a new mGlu7 receptor agonist, LSP2-9166, in my thesis I then studied the impact of this receptor in different epilepsy models in mice. Two complementary models were used: kindling, a chemical model induced by pentylenetetrazol (PTZ) which sensitizes the brain to induce generalized tonic-clonic seizures, and intra-hippocampal injection of kainate, mimicking mesial temporal lobe epilepsy in humans.At first, I observed an attenuation of the progression of the seizures severity in the PTZ kindling model, under the activation of the mGlu7 receptor. This effect was correlated with weaker inflammation, and microglial and astrocytic activation. In the intra-hippocampal injection model of KA, considered as drug-resistant, activation of the mGlu7 receptor during the epileptogenesis period increased the duration of interictal periods and decreased the duration of seizures as well as neuronal reorganization. Once chronic seizures were established, acute activation of the mGlu7 receptor decreased the number of seizures as strongly as diazepam, commonly used in clinical settings. Finally, chronic injections of LSP2-9166 into naive (non epileptic) animals do not generate any detectable cognitive or behavioral deficits or changes in mGlu7 receptor mRNA level. The activation of the mGlu7 receptor thus presents a strategic target in our two models.This work provides a better understanding of the role of the mGlu7 receptor in epileptogenesis. It participates in the search for future more adequate treatments
Murat, Samy. „La phosphorylation du récepteur mGlu₂ du glutamate : mécanisme clé de son cross talk fonctionnel avec le récepteur 5-HT2A de la sérotonine“. Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT002/document.
Der volle Inhalt der QuelleThe serotonin 5-HT2A and glutamate mGlu2 receptors keep on attracting particular attention given their implication in psychosis associated with schizophrenia and in the mechanism of action of atypical antipsychotics and of a new class of antipsychotics, respectively. Though atypical antipsychotics, targeting 5-HT2A receptor, are efficient against positive symptoms, these drugs do not act against negative, cognitive symptoms and display many side effects. Since the 90’s, new classes of antipsychotics triggering glutamatergic system, in particular mGlu2 receptor, have been developed. Their clinical trials have shown efficacy only in patients who have not been previously treated with atypical antipsychotics. This suggests a strong interaction between 5-HT2A and mGlu2 receptors in the mechanism of action of both classes of antipsychotics. Moreover, a large body of evidence indicates the presence, in prefontal cortex, of 5-HT2A/mGlu2 heteromer that is important for the response to hallucinogens and antipsychotics targeting one receptor or the other. Thus, in view of the importance of the phosphorylation profile adopted by G-protein coupled receptor (GPCR) on their activity, I characterized the impact of 5-HT2A receptor co-expression on the phosphorylation profile of mGlu2 receptor in response to various stimulations. Among the five identified phosphorylated residues, the phosphorylation of Ser843 increases upon mGlu2 receptor stimulation only when the 5-HT2A receptor is co-expressed. A new antibody against the phosphorylated form of Ser843 confirmed these results in HEK-293 cells and in mouse prefrontal cortex, area where both receptors are co-expressed. Functional studies demonstrated that Ser843 phosphorylation is necessary to enhance Gi/o signaling of mGlu2 receptor and constitutes a functional crosstalk between 5-HT2A and mGlu2 receptor since 5-HT2A receptor agonists also stimulate Ser843 phosphorylation. Collectively, my thesis findings identify mGlu2 receptor phosphorylation at Ser843 as a key molecular event of the functional crosstalk with 5-HT2A receptor that might be critical to understand the mechanism of action of atypical and potential future antipsychotics treatments
Bessis, Anne-Sophie. „Construction et validation d'un modèle d'activation des récepteurs métabotropiques du glutamate (mGluR)“. Paris 5, 2002. http://www.theses.fr/2002PA05P608.
Der volle Inhalt der QuelleMetabotropic glutamate receptors (mGluRs) belong to the G-Protein-Coupled-Receptors (GPCR) superfamily that constitute about 1% of human genome. They own seven transmembranar domains, but are distinct from GPCRs of family 1 (rhodopsin-like receptor family) or family 2 (glucagon-like receptor family). In fact, the eight human mGluRs form a new GPCR family , family 3 and display a few singularities. For example, these proteins possess a large extracellular domain, which binds the natural ligand glutamate. According to low sequence homologies detected between this domain and bacterial periplasmic proteins, LIVBP, LBP (Leucine/Isoleucine/Valine Binding Protein and Leucine Binding Protein), a structural model of this domain has been built by homology modeling and the glutamate binding site of mGluRs has been identified. Structurally, this domain folds into two lobes that open and close as a clamshell. Functionnally, this study led us to conclude that the the closure of the two lobes, which is stabilized by glutamate fixation, is necessary for mGluR activity. .
Goyet, Elise. „Dynamique et fonction des interactions entre récepteurs du glutamate et de la dopamine“. Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT019.
Der volle Inhalt der QuelleIn some specific brain areas, synergism between glutamate and dopamine transmission is required to induce synaptic plasticity. Metabotropic glutamate receptor mGlu5 and dopamine receptor D1 are both known to control synaptic plasticity. Moreover, multiple lines of evidence converge toward the ability of G-protein coupled receptors to form dynamic heteromers thereby creating new entities with unique properties. Focusing on the hypothesis of receptor heteromerization, my PhD project aimed at investigating the molecular mechanisms underlying a functional interplay between mGlu5 and D1 receptors.To address this issue, a first part of this work consisted in improving single-cell Bioluminescent Resonance Energy Transfer (BRET) imaging, a technology enabling to study real time protein-protein interaction dynamics in living cells. Using the Nanoluciferase, an extremely bright luciferase, we characterized a faster and higher resolution single-cell BRET imaging technique with unprecedented performance in terms of temporal and spatial resolution, duration of signal stability and signal sensitivity. In the second part of this project, we showed that mGlu5 and D1 can form heteromers in heterologous expression system. The above-mentioned improvements of single-cell BRET imaging technique allowed to evidence the occurrence and the dynamics of mGlu5/D1 heteromers in cultured primary neurons. Furthermore, our results showed that the co-expression of mGlu5 and D1 receptors modifies single receptor properties to favor calcium signaling by increasing mGlu5 constitutive activity and creating a D1 agonist-induced activation of Ca2+ release from intracellular stores.These findings advance our knowledge about the molecular basis of the glutamate/dopamine functional dialogue to control neuronal communication in physiological conditions. Further investigation will help the dissection of the mGlu5/D1 heteromer specific signaling pathway with the hope of defining new therapeutics that may selectively modulate heteromer function and thus bypass undesirable side effects
Bolteau, Raphaël. „Conception, synthèse et évaluation pharmacologique d’antagonistes des récepteurs A2A et de ligands duaux ciblant les récepteurs A2A et mGlu5“. Thesis, Lille 2, 2020. http://www.theses.fr/2020LIL2S006.
Der volle Inhalt der QuelleThe past fifty years have been marked by the breakthrough of neurodegenerative diseases such as Alzheimer’s. Unfortunately, only symptomatic treatments are available. Furthermore, facing this multifactorial disease, the search for new and innovative therapeutic targets becomes a major challenge. Among these targets, the adenosine A2A receptor (A2AR) has been the subject of much research in recent years. Indeed, it has been shown that A2AR antagonists such as caffeine improve memory performance as it reduces β-amyloid deposits and Tau-phosphorylation. Though several A2AR antagonists have reached clinical trials, current research efforts are focused on developing new antagonists with relevant ADME properties. On the other hand, negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5) also play an important role in the pathological conditions associated with Alzheimer’s disease. It has been found that blocking the activity of mGlu5 reduces the neurotoxicity and synaptoxicity of the amyloid peptide in vitro but also in vivo. Based on a molecular modeling-guided design, we developed new A2AR antagonists with quinazoline and benzofuran as central scaffold and a dual ligands strategy targeting both A2A and mGlu5 receptors. Hit-to-lead optimization has led to nanomolar affinity compounds for A2AR and a new co-crystallized structure. Among them, some hit compounds have been identified with micromolar affinities towards mGluR5
Philibert, Clémentine. „Le récepteur métabotropique du glutamate mGlu2 interagit avec et transactive le récepteur tyrosine kinase TrkB : rôle dans la réponse comportementale aux antipsychotiques glutamatergiques“. Thesis, Université de Montpellier (2022-….), 2022. http://www.theses.fr/2022UMONT019.
Der volle Inhalt der QuelleSchizophrenia is a multifactorial debilitating mental disorder affecting 1 % of the world population characterized by three classes of symptoms: positive symptoms (e.g. hallucinations), negative symptoms (e.g. social isolation) and cognitive deficits (e.g. impaired working memory). Current antipsychotics such as typical and atypical antipsychotics, targeting dopamine D2 receptor and serotonin 5-HT2A receptor respectively, are able to treat efficiently the positive symptoms and partially the negative symptoms. However, antipsychotics treating efficiently the three classes of symptoms is still an unmet need. The metabotropic glutamate mGlu2 receptor (mGluR2) keeps on attracting particular attention given its implication in schizophrenia. This G protein-coupled receptor (GPCR) is the main target of a new generation of antipsychotics currently under clinical trial, treating efficiently the three class of symptoms without displaying any side effects. However, mGluR2 signaling in the brain and its pathological disturbances remain poorly characterized. Specific characterization of mGluR2 signaling in the brain was previously challenging due to a high homology of sequences with the structurally close metabotropic glutamate mGluR3 receptor, which complicated the production of specific ligands or antibodies. We have taken advantage of a single lama chain antibody (nanobody) specifically targeting mGluR2 in order to purify the endogenous receptor and its interacting proteins from mouse prefrontal cortex, a brain region known to strongly express mGluR2 but also highly disturbed in schizophrenia. This interactome was characterized by high resolution mass spectrometry and bioinformatics annotations of the gene ontologies of the candidate protein partners revealed high relevance to mGluR2 functions. One of these interactors revealed to be very attractive: the receptor tyrosine kinase TrkB. Highly significant in our AP-MS analysis, the mRNA of this rec eptor tyrosine kinase has been shown to be decreased in the brain tissue of patients with schizophrenia in comparison to control tissues. We were able to decipher that: 1) mGluR2 and TrkB interact specifically, 2) this interaction is modulated by the conformational state of both receptors, 3) mGluR2 stimulation by its agonist transactivates TrkB in cortical neurons in the prefrontal cortex, 4) the activation of TrkB leads to the modulation of the canonical activity of mGluR2 and 5) the antipsychotic-like effects of mGluR2 agonists in preclinical model of schizophrenia are mediated by TrkB for negative and cognitive deficits rescue. In summary, this reciprocal transactivation of mGluR2 and TrkB is highly promising and might have a pathophysiological influence in psychosis such as schizophrenia, but most importantly, TrkB has a pivotal role in mediating the antipsychotic-like effect of mGluR2 ligand for symptoms resisting so far to current antipsychotics
Perroy, Julie. „Le récepteur métabotropique du glutamate mGlu7 : voie de signalisation et fonction dans les neurones“. Montpellier 2, 2001. http://www.theses.fr/2001MON20095.
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