Pharmacological dissociation of glutamatergic metabotropic signal transduction pathways in cortical astrocytes.
Using cultured cortical astrocytes we demonstrate differential activation of metabotropic signal transduction pathways with 1-aminocyclopentane-trans-1S3R-dicarboxylic acid (1S3R-ACPD) and the glutamate transport 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 efficacious than 1S3R-ACPD at inhibiting cyclic AMP accumulation. The metabotropic receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine ((+)-MCPG) inhibited 1S3R-ACPD stimulation of phosphoinositide hydrolysis but not its ability to inhibit cyclic AMP accumulation thereby demonstrating 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 this compound to inhibit glutamate uptake. Taken together the findings indicate the presence of multiple glutamatergic signal transduction pathways in astrocytes and suggest a similarity in the pharmacophores for metabotropic receptors and glutamate transporters.
Department of Psychobiology, Irvine Research Unit in Brain Aging, University of California 92717-4550.
S
S
Miller
R J
RJ
Bridges
A R
AR
Chamberlin
C W
CW
Cotman
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D009457:Neuroglia / Q000378:metabolism; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D011759:Pyrrolidines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
D001565:Benzoates; D003998:Dicarboxylic Acids; D009498:Neurotoxins; D010716:Phosphatidylinositols; D011759:Pyrrolidines; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; C079694:alpha-methyl-4-carboxyphenylglycine; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D000242:Cyclic AMP; D007545:Isoproterenol; D005998:Glycine