Altered protein phosphorylation in intact rat cortical synaptosomes after in vivo administration of fluphenazine.
Phenothiazines such as fluphenazine are able to inhibit calcium-stimulated protein kinases in vitro in both lysed and intact synaptosomes. In this study protein phosphorylation was assayed in intact synaptosomes isolated from the cerebral cortex of rats treated chronically (21 days, 10 mg/kg, i.p.) or acutely (1 hr, 10 mg/kg, i.p.) with fluphenazine. When intact synaptosomes from chronically treated animals were prelabeled with 32Pi, there were two effects on protein phosphorylation: an increase in the basal labeling of many phosphoproteins and a decrease in depolarization-evoked protein phosphorylation. Acute injections had even more pronounced effects, but the direction and nature of the effects were the same. No effects on K+-stimulated calcium entry or on protein phosphatase activity were detected. When lysed synaptosomes from chronically treated animals were labeled in the presence of [gamma-32P]ATP, a small decrease in calmodulin-dependent and cAMP-dependent protein phosphorylation was observed. The results suggest that two different in vivo mechanisms may underlie these effects, and these are discussed. We proposed that intact synaptosomes may be a good model in which to study the in vivo mechanisms of the action of fluphenazine since they appear to retain at least some effects of the drug after subcellular fractionation.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000494:pharmacology; D004594:Electrophysiology; D005476:Fluphenazine / Q000494:pharmacology*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism*; D011188:Potassium / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013574:Synaptosomes / Q000378:metabolism*
D002147:Calmodulin; D010750:Phosphoproteins; D000242:Cyclic AMP; D011494:Protein Kinases; D011188:Potassium; D005476:Fluphenazine; D002118:Calcium