Premium
Metabotropic Glutamate Receptor mGluR5 in Astrocytes: Pharmacological Properties and Agonist Regulation
Author(s) -
Balázs Robert,
Miller Stephan,
Romano Carmelo,
De Vries Annick,
Chun Yong,
Cotman Carl W.
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69010151.x
Subject(s) - metabotropic glutamate receptor 5 , metabotropic glutamate receptor 1 , metabotropic glutamate receptor , homologous desensitization , agonist , metabotropic glutamate receptor 6 , metabotropic glutamate receptor 7 , metabotropic glutamate receptor 4 , biology , protein kinase c , metabotropic receptor , microbiology and biotechnology , metabotropic glutamate receptor 3 , receptor , chemistry , pharmacology , biochemistry , signal transduction
Metabotropic glutamate receptor (mGluR) agonists induce extensive phosphoinositide (PI) hydrolysis in astrocytes grown in a chemically defined medium with select growth factors. These astrocytes express mGluR5 transcripts, but none of the splice variants of mGluR1, thus permitting the characterization of mGluR5 in a native CNS cell without interference from mGluR1 activity. mGluR5 activation (1) was not associated with stimulation of cyclic AMP formation, (2) showed high sensitivity to the removal of extracellular versus intracellular Ca 2+ , (3) displayed high coupling efficiency relative to receptor density, and (4) induced PI hydrolysis that was suppressed by phorbol esters with low potency. The rank order of agonist potency was similar to that observed in mGluR1 and mGluR5 transfected cells. The phenylglycine antagonists tested were effective in blocking responses to 1‐aminocyclopentane‐1 S ,3 R ‐dicarboxylic acid, but not to glutamate. Prolonged exposure to agonists induced a two‐phase desensitization of mGluR5 function, an initial phase (completed by 1 h and plateaus for another 3 h) and a late phase (progressive decrease to ∼30% of control levels by 24 h). Only the latter phase was associated with receptor down‐regulation. Desensitization of mGluR5 function did not involve receptor internalization or phosphorylation mediated by protein kinase C or A; it was purely homologous, and reversible. Resensitization after short agonist treatment did not require prior receptor sequestration. Recovery after prolonged agonist exposure required new protein synthesis, but the restoration of function was more rapid than normalization of receptor protein levels, indicating that regulation also involves other components of the transduction system. The protracted desensitization of mGluR5 in astrocytes suggests that the functions mediated by this receptor are maintained under a variety of conditions ranging from repetitive stimulation to injury responses.