R. Balazs et al., METABOTROPIC GLUTAMATE-RECEPTOR MGLUR5 IN ASTROCYTES - PHARMACOLOGICAL PROPERTIES AND AGONIST REGULATION, Journal of neurochemistry, 69(1), 1997, pp. 151-163
Metabotropic glutamate receptor (mGluR) agonists induce extensive phos
phoinositide (PI) hydrolysis in astrocytes grown in a chemically defin
ed medium with select growth factors, These astrocytes express mGluR5
transcripts, but none of the splice variants of mGluR1, thus permittin
g the characterization of mGluR5 in a native CNS cell without interfer
ence from mGluR1 activity. mGluR5 activation (I) was not associated wi
th stimulation of cyclic AMP formation, (2) showed high sensitivity to
the removal of extracellular versus intracellular Ca2+, (3) displayed
high coupling efficiency relative to receptor density, and (4) induce
d PI hydrolysis that was suppressed by phorbol esters with low potency
. The rank order of agonist potency was similar to that observed in mG
luR1 and mGluR5 transfected cells. The phenylglycine antagonists teste
d were effective in blocking responses to 1-aminocyclopentane-1 S,3R-d
icarboxylic acid, but not to glutamate, Prolonged exposure to agonists
induced a two-phase desensitization of mGluR5 function, an initial ph
ase (completed by 1 h and plateaus for another 3 h) and a late phase (
progressive decrease to similar to 30% of control levels by 24 h), Onl
y the latter phase was associated with receptor down-regulation, Desen
sitization of mGluR5 function did not involve receptor internalization
or phosphorylation mediated by protein kinase C or A; it was purely h
omologous, and reversible, Resensitization after short agonist treatme
nt did not require prior receptor sequestration. Recovery after prolon
ged agonist exposure required new protein synthesis, but the restorati
on of function was more rapid than normalization of receptor protein l
evels, indicating that regulation also involves other components of th
e transduction system, The protracted desensitization of mGluR5 in ast
rocytes suggests that the functions mediated by this receptor are main
tained under a variety of conditions ranging from repetitive stimulati
on to injury responses.