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Inhibition by Cyclic AMP of Phorbol Ester‐Potentiated Norepinephrine Release from Guinea Pig Brain Cortical Synaptosomes
Author(s) -
Shuntoh Hisato,
Taniyama Kohtaro,
Fukuzaki Hisashi,
Tanaka Chikako
Publication year - 1988
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1988.tb01126.x
Subject(s) - protein kinase c , forskolin , staurosporine , protein kinase a , activator (genetics) , chemistry , phorbol , synaptosome , endocrinology , medicine , protein kinase inhibitor , guinea pig , biology , calcium , biochemistry , kinase , stimulation , receptor
The involvement of Ca 2+ /pnospholipid‐dependent protein kinase (protein kinase C, PKC) and cyclic AMP‐de‐pendent protein kinase in the K + ‐evoked release of norepinephrine (NE) was studied using guinea pig brain cortical synaptosomes preloaded with [ 3 H]NE. 12‐ O ‐Tetradecanoyl‐phorbol‐13‐acetate (TPA), a potent activator of PKC, enhanced the K + ‐evoked release of [ 3 H]NE, in a concentration‐dependent manner, but with no effect on the spontaneous outflow and uptake of [ 3 H]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 po‐tentiation 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 Ca 2+ ‐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 neu‐rotransmitter release process in brain synaptosomes of the guinea pig.