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Glutamates --- Neurotransmitters --- Glutamates. --- Neurotransmitters. --- Cell membrane --- Synaptic receptors. --- Physiological effect --- Congresses. --- Congresses. --- Physiology.
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Mitochondria, Liver --- Glutamates --- Adenosine Diphosphate --- drug effects --- metabolism --- blood
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Glutamates --- Glutamic acid --- Monosodium glutamate --- Physiology --- Metabolism --- Physiological effect --- Effets physiologiques --- Glutamates. --- physiology. --- MSG (Food additive) --- Sodium glutamate --- Food additives --- Sodium salts --- Glutamate --- Excitatory amino acids --- Umami (Taste)
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The amino acid I-glutamate is the major excitatory neurotransmitter in the mammalian nervous system. It is also involved in memory and learning functions as well as in neuronal plasticity. Extracellular concentrations of glutamate must be tightly regulated to avoid excitotoxicity and neuronal death. The absence of enzyme that can metabolise glutamate in the synaptic cleft requires that the active removal of this amino acid specific transporters proteins. Glutamate is essentially taken up by astrocytes. The uptake is not constant as it is regulated by different mechanisms affecting transporters expression, localisation or activity.
In the literature, intracellular trafficking of receptors, transporters and channels is often dependent on interactions with scaffold proteins. These are characterized by one or more PDZ domains that can bind the C-terminus of protein partners. PICK1 with its single PDZ domain plays a critical role in the regulation of glutamatergic transmissions via interaction with matebotropic and ionotropic receptors. PICK1 has also the ability to interact simultaneously with PKCα and other partners, to homo-oligomerise and bind to membrane lipids. This prompted us to study the role of PICK1 in modulating glutamate transport activity in astrocytes.
Here we show that this protein is endogenously expressed in astrocytes. Furthermore, this expression tends to increase when astrocytes are maintained in a medium that chemically mimics pathologic environment. By transient transfection with plasmids coding wild-type or mutated PICK1 we show evidence that PICK1 stimulates glutamate uptake. Using pharmacological inhibitors, we demonstrated that the high affinity glutamate transporterGLT-1, is implicated in the increase of glutamate uptake. Furthermore, this effect is not observed when the PDZ domain of PICK1 is altered. Taking together, these results suggest that PICK1 could participate in the regulation of uptake activity, an effect that could involve specific interaction between GLT-1 and the PDZ domain of PICK1. Considering he induction of PICK1 expression in chemically activated astrocytes, these data could suggest a critical role for PICK1 in astrocytes activity within a pathologic context L’acide amine L-glutamate est le neurotransmetteur excitateur majeur du système nerveux central des mammifères. Il est également impliqué dans les processus de mémorisation, d’apprentissage et de plasticité neuronale. Sa concentration extracellulaire doit être finement régulée afin d’éviter les phénomènes d’excitotoxicité entraînant la mort neuronale. L’absence d’enzyme spécifique de la dégradation du glutamate au sein de la fente synaptique nécessite qu’il soit éliminé grâce à des protéines spécifiques : les transporteurs du glutamate. Cette capture est essentiellement astrocytaire. Elle n’est pas constante et peut être modulée par différents mécanismes qui contribuent à modifier l’expression, la localisation cellulaire et l’activité des transporteurs.
Dans la littérature, l’adressage des récepteurs, transporteurs et canaux vers la membrane est souvent dépendant de l’interaction avec des protéine d’achafaudage. Ces protéines sont caractérisées par la présence d’un ou de plusieurs domaines PDZ spécialisés dans la reconnaissance de partenaires protéiques au niveau de leur extrémité carboxyterminale. La protéine PICK1 (Protein Interacting with C kinase 1), à domaine PDZ unique, participe activement à la régulation de la transmission glutamatergiguqe via l’adressage des récepteurs métabotropiques et ionotropiques du glutamate vers la membrane neuronale. Sa capacité à lier simultanément la PKCα et ses partenaires protéiques, de s’homo-oligomériser ainsi que de se lier aux lipides membranaires nous a incité à étudier une éventuelle influence de PICK1 sur l’activité des transporteurs du glutamate dans les astricytes.
Nous avons pu montrer que cette protéine est naturellement exprimée dans les astrocytes en culture. De plus, cette expression augmente lorsque les astrocytes sont soumis à des conditions mimant un environnement lésionnel et favorisant leur activation. D’autre part, en surexprimant la protéine PICK1 par transfection transitoire, nous avons pu mettre en évidence une augmentation très significative de la capture du glutamate. L’utilisation d’outils pharmacologiques a démontré l’implication du transporteur du glutamate GLT-1 dans l’augmentation de l’activité de capture. Par ailleurs, cet effet n’est pas observable après surexpression d’un mutant de PICK1 inactivé au sein du domaine PDZ. Ces résultats suggèrent que PICK1 présent dans les astrocytes participe à la régulation de l’activité de capture du glutamate et que cette régulation pourrait impliquer l’interaction de GLT-1 avec les astrocytes activés, ces données pourraient suggérer un rôle critique de cette protéine dans la régulation de l’activité des astrocytes dans un constexte pathologique
PICK1 protein, human --- Amino Acid Transport --- Systel X-AG --- Glutamates --- Neurotransmitter Agents --- Astrocytes
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Glutamates --- Synaptic Transmission --- Neurotransmitter Agents --- Septum Pellucidum --- pharmacology --- drug effects --- physiology --- physiology
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Excitatory amino acids --- Neurotransmitters --- Glutamates --- Neuroregulators --- Receptors, Synaptic --- Physiological effect --- Congresses. --- pharmacology --- congresses. --- drug effects --- Congresses --- Amino acids --- Receptors
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Ethanol --- Brain --- Food Additives --- Glutamates --- Hyperkinesis --- Metabolism, Inborn Errors --- Peptides --- adverse effects --- physiopathology --- adverse effects --- adverse effects --- etiology --- physiopathology --- adverse effects
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Arthropod Venoms --- Axons --- Glutamates --- Grasshoppers --- Spider Venoms --- Neuroglia --- Polyamines --- Structure-Activity Relationship --- Synaptic Transmission --- pharmacology --- drug effects --- metabolism --- drug effects --- pharmacology --- drug effects --- pharmacology
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Enzymes. --- Glutamates. --- Glutamine. --- Glutathione. --- Reduced Glutathione --- gamma-L-Glu-L-Cys-Gly --- gamma-L-Glutamyl-L-Cysteinylglycine --- Glutathione, Reduced --- gamma L Glu L Cys Gly --- gamma L Glutamyl L Cysteinylglycine --- D-Glutamine --- L-Glutamine --- D Glutamine --- L Glutamine --- Glutamic Acid Derivatives --- Glutamic Acids --- Glutaminic Acids --- Biocatalysts --- Molecular Mechanisms of Pharmacological Action --- Glutamate decarboxylase --- Glutamine --- Glutathione --- Glutamates --- Biological techniques --- Enzymology --- Enzymes --- Glutathion --- Glutamate. --- Glutamaat. --- Biocatalyst --- Enzyme
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Monosodium glutamate --- Taste --- Flavor --- Goût --- Saveur --- Physiological effect --- Congresses --- Effets physiologiques --- Congrès --- Flavoring Agents. --- Food Additives. --- Food Preferences. --- Glutamates. --- -Taste --- -Gustation --- Tasting (Physiology) --- Chemical senses --- Drinking behavior --- Senses and sensation --- Tongue --- Food preferences --- MSG (Food additive) --- Sodium glutamate --- Food additives --- Glutamic acid --- Sodium salts --- Glutamic Acid Derivatives --- Glutamic Acids --- Glutaminic Acids --- Food Selection --- Food Preference --- Food Selections --- Preference, Food --- Preferences, Food --- Selection, Food --- Selections, Food --- Additive, Food --- Additives, Food --- Food Additive --- Agent, Flavoring --- Agents, Flavoring --- Flavoring Agent --- physiology. --- Congresses. --- -Congresses --- -physiology. --- Goût --- Congrès --- Umami (Taste) --- Flavoring Agents --- Food Additives --- Food Preferences --- Glutamates --- Flavor Additives --- Flavor Enhancers --- Additive, Flavor --- Additives, Flavor --- Enhancer, Flavor --- Enhancers, Flavor --- Flavor Additive --- Flavor Enhancer --- Gustation --- physiology
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