A 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 Ca2+-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 Ca2+ concentration ([Ca2+](c)) and in forskolin-stimulated cAMP formation. However, the reduction in [Ca2+](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.