PHARMACOLOGICAL DISSOCIATION OF GLUTAMATERGIC METABOTROPIC SIGNAL-TRANSDUCTION PATHWAYS IN CORTICAL ASTROCYTES

Using cultured cortical astrocytes we demonstrate differential activat ion of metabotropic signal transduction pathways with 1-aminocyclopent ane-trans-1S3R-dicarboxylic acid (1S3R-ACPD) and the glutamate transpo rt inhibitor trans-2,4-pyrrolidine dicarboxylic acid (trans-2,4-PDC). Phosphoinositide hydrolysis was more potently stimulated by 1S3R-ACPD than by L-trans-2,4-PDC; however, L-trans-2,4-PDC was far more efficac ious than 1S3R-ACPD at inhibiting cyclic AMP accumulation. The metabot ropic receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+) -MCPG) inhibited 1S3R-ACPD stimulation of phosphoinositide hydrolysis but not its ability to inhibit cyclic AMP accumulation thereby demonst rating a means to pharmacologically dissociate these two metabotropic signal transduction pathways in astrocytes. (+)-MCPG produced similar antagonism of the metabotropic agonist properties of L-trans-2,4-PDC. The metabotropic effects of L-trans-2,4-PDC could not be reduced with enzymatic treatment of the cultures to remove extracellular glutamate, suggesting that these effects are not secondary to the ability of thi s compound to inhibit glutamate uptake. Taken together the findings in dicate the presence of multiple glutamatergic signal transduction path ways in astrocytes and suggest a similarity in the pharmacophores for metabotropic receptors and glutamate transporters.