Staurosporine counteracts the phorbol ester-induced enhancement of neurotransmitter release in hippocampus.
The effects of staurosporine, introduced as a very potent inhibitor of protein kinase C (PKC), on evoked neurotransmitter release were investigated and compared with those of the other PKC inhibitors: 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) and polymyxin B (PMB). Slices of rabbit hippocampus, prelabelled with either [3H]noradrenaline, [3H]5-hydroxytryptamine or [3H]choline were superfused with physiological medium. During superfusion the slices were stimulated either electrically (3 Hz, 5 V/cm, 24 mA, 2 msec) or by high K+ (30 mM) for 2 min, respectively. Both the electrically and potassium evoked overflow were increased by the PKC activator 4 beta-phorbol 12,13-dibutyrate (PDB). The degree of the enhancement by PDB was dependent on the transmitter and the stimulation conditions used. These results may be explained by differences in the extent of activation of PKC during electrically or potassium evoked release. The PDB-induced enhancement of electrically or potassium evoked release of the 3 transmitters was counteracted by staurosporine (1 microM) in concentrations much lower than those required for H7 (100 microM) and PMB (100 microM). PMB, which has been shown to decrease electrically evoked transmitter release, similarly diminished K+-evoked release. In contrast, only the potassium evoked [3H]acetylcholine release was significantly diminished by staurosporine (1 microM) and H7 (100 microM). In conclusion, these results show again that facilitation of neurotransmitter release by phorbol esters is due to activation of PKC.
Daschmann
B
B
Institute of Pharmacology, Freiburg i. Br., F.R.G.
Allgaier
C
C
Nakov
R
R
Hertting
G
G
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000109:Acetylcholine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010703:Phorbol Esters / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011112:Polymyxin B / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism; D019311:Staurosporine
D000470:Alkaloids; D007546:Isoquinolines; D018377:Neurotransmitter Agents; D010703:Phorbol Esters; D010879:Piperazines; D012701:Serotonin; D015240:Phorbol 12,13-Dibutyrate; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011493:Protein Kinase C; D019311:Staurosporine; D011112:Polymyxin B; D000109:Acetylcholine; D011188:Potassium; D009638:Norepinephrine