Further evidence of Ca(2+)-dependent, exocytotic-like serotonin release induced by D-fenfluramine.
The effect of polymyxin B and KN-62 on the [3H]5-HT release induced by depolarization and by 0.5 microM D-fenfluramine (dF) from superfused rat hippocampal synaptosomes was examined. Polymyxin B and KN-62 were initially characterized as inhibitors, respectively, of calmodulin (CaM) and Ca2+/CaM-dependent protein kinase II (Ca/CaM-KII), although both compounds were subsequently described as inhibitors of the depolarization-induced Ca2+ influx through voltage-operated Ca2+ channels, at concentrations similar to those interacting with the CaM systems. Three micromolar KN-62 significantly inhibited the dF- and the depolarization-induced [3H]5-HT release, by 25% and 33%. Polymyxin B, tested at concentrations from 30 to 1000 IU ml-1, dose-dependently inhibited both the dF- and the depolarization-induced [3H]5-HT release with similar potency, with complete inhibition at the highest concentration tested. These compounds did not significantly alter 5-HT transporter function. Moreover dF had no direct effect on Ca/CaM-KII activity. These results further support the suggestion that the [3H]5-HT release induced by low concentrations of dF (0.5 microM), previously found to be Ca(2+)-dependent, actually involves a dF-induced Ca2+ influx into the nerve terminal and the subsequent exocytosis.
Cinquanta
M
M
Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Frittoli
E
E
Mennini
T
T
Gobbi
M
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects*; D005277:Fenfluramine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D011112:Polymyxin B / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000900:Anti-Bacterial Agents; D002118:Calcium; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D005277:Fenfluramine; D011112:Polymyxin B; D011189:Potassium Chloride; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C063302:KN 62