Abstract
The metabotropic glutamate receptor 5 (mGluR5) exhibits a rapid loss of receptor responsiveness to prolonged or repeated agonist exposure. This receptor desensitization has been seen in a variety of native and recombinant systems, and is thought to result from receptor-mediated, protein kinase C (PKC)-dependent phosphorylation of the receptor, uncoupling it from the G protein in a negative feedback regulation. We have investigated the rapid PKC-mediated desensitization of mGluR5 in cortical cultured astrocytes by measuring downstream signals from activation of mGluR5. These include activation of phosphoinositide (PI) hydrolysis, intracellular calcium transients, and extracellular signal-regulated kinase 2 (ERK2) phosphorylation. We present evidence that PKC plays an important role in rapid desensitization of PI hydrolysis and calcium signaling, but not in ERK2 phosphorylation. This differential regulation of mGluR5-mediated responses suggests divergent signaling and regulatory pathways which may be important mechanisms for dynamic integration of signal cascades.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Astrocytes / cytology
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Astrocytes / metabolism*
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Calcium Signaling / physiology
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Cells, Cultured
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Enzyme Activation / drug effects
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Enzyme Activators / pharmacology
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agonists / pharmacology
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Glycine / analogs & derivatives
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Glycine / pharmacology
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Hydrolysis / drug effects
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Isoenzymes / metabolism
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Mitogen-Activated Protein Kinase 1 / metabolism*
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Phosphatidylinositols / metabolism*
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Phospholipase C beta
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Phosphorylation / drug effects
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Protein Kinase C / drug effects
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Protein Kinase C / metabolism*
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Rats
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Rats, Sprague-Dawley
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / metabolism*
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Resorcinols / pharmacology
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Type C Phospholipases / metabolism
Substances
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Enzyme Activators
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Grm5 protein, rat
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Isoenzymes
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Phosphatidylinositols
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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Resorcinols
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3,5-dihydroxyphenylglycine
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Protein Kinase C
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Mitogen-Activated Protein Kinase 1
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Type C Phospholipases
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Phospholipase C beta
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Glycine