PHOSPHORYLATION OF MITOGEN-ACTIVATED PROTEIN-KINASE IN CULTURED RAT CORTICAL GLIA BY STIMULATION OF METABOTROPIC GLUTAMATE RECEPTORS

Activation of metabotropic glutamate receptors (mGluRs) in glia result s in significant physiological effects for both the glia and the neigh boring neurons; but in many cases, the mGluR subtypes and signal trans duction mechanisms mediating these effects have not been determined. I n this study, we report that mGluR activation in primary cultures of r at cortical glia results in tyrosine phosphorylation of several protei ns, including p44/p42 mitogen-activated protein kinases, also referred to as extracellular signal-regulated kinases (ERK1/2), Incubation of glial cultures with the general mGluR agonist 1-aminocyclopentane-1S,3 R-dicarboxylate and the mGluR group I-selective agonists (RS)-3,5-dihy droxyphenylglycine (DHPG) and L-quisqualate resulted in increased tyro sine phosphorylation of ERK1/2, The group Ii-selective agonist (2S,2'R ,3'R)-2-(2',3'-dicarboxycyclopropyl) glycine and group III-selective a gonist L(+)-2-amino-4-phosphonobutyric acid had no effect on tyrosine phosphorylation, DHPG-induced ERK1/2 phosphorylation could be inhibite d by an antagonist that acts at group I or group II mGluRs but not by antagonists for group II and group III mGluRs, Protein kinase C (PKC) activators also induced ERK1/2 phosphorylation, but the PKC inhibitor bisindolylmaleimide I did not inhibit DHPG-induced ERK1/2 phosphorylat ion at a concentration that inhibited the response to phorbol 12,13-di butyrate, These data suggest that mGluR activation of ERK1/2 in cultur ed glia is mediated by group I mGluRs and that this effect is independ ent of PKC activation. Furthermore, immunoblots with antibodies agains t various mGluR subtypes show expression of mGluR5, but no other mGluR s in our cultures. Taken together, these results suggest that mGluRS s timulation results in tyrosine phosphorylation of ERK1/2 and other gli al proteins.