Decrease in [Ca2+]c but not in cAMP Mediates L-AP4 inhibition of glutamate release: PKC-mediated suppression of this inhibitory pathway.
We investigated the mechanism of the inhibition of glutamate release by (L)-2-amino-4-phosphonobutyrate ((L)-AP4) in cerebrocortical nerve terminals from young rats (3 weeks of age). The Ca(2+)-dependent release of glutamate was reduced by (L)-AP4 in a concentration-dependent manner. This inhibitory effect was prevented by pertussis toxin, insensitive to staurosporine and associated with a reduction both in the depolarization-evoked increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](c)) and in forskolin-stimulated cAMP formation. However, the reduction in [Ca(2+)](c) but not in cAMP seemed to be responsible for the decrease in release, since inhibition by (L)-AP4 can also be observed in the absence of detectable changes in cAMP The inhibitory modulation by (L)-AP4 was suppressed by the activation of protein kinase C with phorbol esters. The nerve terminals from young rats also exhibited a facilitatory pathway of glutamate release which was mediated by protein kinase C. Interestingly, stimulation of this pathway with the glutamate agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate in the presence of arachidonic acid also abolished the inhibitory action of (L)-AP4. The dominance of the facilitatory pathway in its interaction with the (L)-AP4-mediated inhibitory control may provide some clues to understand the presynaptic changes during synaptic plasticity.
Herrero
I
I
Departamento de Bioquímica, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain.
Vázquez
E
E
Miras-Portugal
M T
MT
Sánchez-Prieto
J
J
D000613:Aminobutyrates / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003593:Cytoplasm / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists; D009994:Osmolar Concentration; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000613:Aminobutyrates; D018691:Excitatory Amino Acid Antagonists; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D000242:Cyclic AMP; D011493:Protein Kinase C; C012729:2-amino-4-phosphonobutyric acid; D002118:Calcium