Inhibition by cyclic AMP of phorbol ester-potentiated norepinephrine release from guinea pig brain cortical synaptosomes.
The involvement of Ca2+/phospholipid-dependent protein kinase (protein kinase C, PKC) and cyclic AMP-dependent protein kinase in the K+-evoked release of norepinephrine (NE) was studied using guinea pig brain cortical synaptosomes preloaded with [3H]NE. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a potent activator of PKC, enhanced the K+-evoked release of [3H]NE, in a concentration-dependent manner, but with no effect on the spontaneous outflow and uptake of [3H]NE in the synaptosomes. The apparent affinity of the evoked release for added calcium but not the maximally evoked release was increased by TPA (10(-7) M). Inhibitors of PKC, polymyxin B, and a more potent inhibitor, staurosporine, counteracted the TPA-induced potentiation of the evoked release. Both forskolin and dibutyryl cyclic AMP (DBcAMP) enhanced the evoked release, but reduced the TPA-potentiated NE release. A novel inhibitor of cyclic AMP-dependent protein kinase, KT5720, blocked both the forskolin-induced increase in the evoked release and its inhibition of TPA-induced potentiation in the evoked release, thereby suggesting that forskolin or DBcAMP counteracts the Ca2+-dependent release of NE by activating cyclic AMP-dependent protein kinase. These results suggest that the activation of PKC potentiates the evoked release of NE and that the activation of cyclic AMP-dependent protein kinase acts negatively on the PKC-activated exocytotic neurotransmitter release process in brain synaptosomes of the guinea pig.
Shuntoh
H
H
Department of Pharmacology, Kobe University School of Medicine, Japan.
Taniyama
K
K
Fukuzaki
H
H
Tanaka
C
C
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007211:Indoles; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011112:Polymyxin B / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism; D011758:Pyrroles; D019311:Staurosporine; D013574:Synaptosomes / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
D000470:Alkaloids; D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D005576:Colforsin; C057416:KT 5720; D003994:Bucladesine; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D019311:Staurosporine; D011112:Polymyxin B; D013755:Tetradecanoylphorbol Acetate; D011188:Potassium; D009638:Norepinephrine