PRESYNAPTIC MODULATION OF CHOLECYSTOKININ RELEASE BY PROTEIN-KINASE-CIN THE RAT HIPPOCAMPUS

The role of protein kinase C (PKC) in modulating the release of the oc tapeptide cholecystokinin (CCK-8) was investigated in rat hippocampal nerve terminals (synaptosomes). The PKC-activating phorbol eater 4 bet a-phorbol 12,13-dibutyrate (beta-PDBu) dose dependently (5-5,000 nM) i ncreased CCK-8 release in a strictly Ca2+-dependent way. This effect w as observed only when synaptosomes were stimulated with the K-A(+) cha nnel blocker 4-aminopyridine (4-AP; 1 mM) but not with KCl (10-30 mM). The PDBu-induced exocytosis of CCK-8 was completely blocked by the tw o selective PKC inhibitors chelerythrine and calphostin-C and was not mimicked by alpha-PDBu, an inactive phorbol ester. In addition, an ana logue of the endogenous PKC activator diacylglycerol, oleoyl-acetylgly cerol, dose dependently increased CCK-8 exocytosis. beta-PDBU (50-100 nM) also stimulated the 4-AP-evoked Ca2+-dependent release of the clas sic transmitter GABA, which cc-localizes with CCK-8 in hippocampal int erneurons. As a possible physiological trigger for PKC activation, the role of the metabotropic glutamate receptor was investigated. However , the broad receptor agonist (1S,3R)-1-aminocyciopentane-1,3-dicarboxy lic acid did not stimulate, but instead inhibited, both the CCK-8 and the GABA exocytosis. In conclusion, presynaptic PKC may stimulate exoc ytosis of distinct types of colocalizing neurotransmitters via modulat ion of presynaptic K+ channels in rat hippocampus.