Presynaptic modulation of cholecystokinin release by protein kinase C in the rat hippocampus.
The role of protein kinase C (PKC) in modulating the release of the octapeptide cholecystokinin (CCK-8) was investigated in rat hippocampal nerve terminals (synaptosomes). The PKC-activating phorbol ester 4beta-phorbol 12,13-dibutyrate (beta-PDBu) dose dependently (5-5,000 nM) increased CCK-8 release in a strictly Ca2+dependent way. This effect was observed only when synaptosomes were stimulated with the K+(A) channel 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 two selective PKC inhibitors chelerythrine and calphostin-C and was not mimicked by alpha-PDBu, an inactive phorbol ester. In addition, an analogue of the endogenous PKC activator diacylglycerol, oleoylacetylglycerol, dose dependently increased CCK-8 exocytosis. Beta-PDBu (50-100 nM) also stimulated the 4-AP-evoked Ca2+-dependent release of the classic transmitter GABA, which co-localizes with CCK-8 in hippocampal interneurons. 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-aminocyclopentane-1,3-dicarboxylic acid did not stimulate, but instead inhibited, both the CCK-8 and the GABA exocytosis. In conclusion, presynaptic PKC may stimulate exocytosis of distinct types of co-localizing neurotransmitters via modulation of presynaptic K+ channels in rat hippocampus.
Breukel
A I
AI
Institute for Neurobiology, Graduate School of Neurosciences, University of Amsterdam, The Netherlands.
Wiegant
V M
VM
Lopes da Silva
F H
FH
Ghijsen
W E
WE
D000818:Animals; D002766:Cholecystokinin / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D017729:Presynaptic Terminals / Q000502:physiology*; D011493:Protein Kinase C / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology; D012844:Sincalide / Q000378:metabolism; D013574:Synaptosomes / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018094:Receptors, Metabotropic Glutamate; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin; D011493:Protein Kinase C; D012844:Sincalide