Dithiocarbamate propineb induces acetylcholine release through cytoskeletal actin depolymerization in PC12 cells.
Neurological complications as well as movement disorders are relevant symptoms in animals and humans chronically exposed to dithiocarbamates. Using rat pheochromocytoma cells differentiated by NGF (PC12), we investigated whether propineb affects acetylcholine (Ach) release and the molecular mechanisms involved. Propineb (0.001-100 nM) dose-dependently increased Ach release from PC12. Thus, 0.001-1 nM propineb-induced Ach release, reaching a maximal effect ( approximately 50%) at 0.1-1 nM. Higher concentrations of propineb (10-100 nM) caused a progressive disappearance of the effect. Chelation of extra- and intracellular Ca(2+) did not affect Ach release by propineb, which was prevented by the actin stabilizer jasplakinolide (500 nM). Accordingly, actin depolymerization was observed after exposure of differentiated PC12 to 0.1-1 nM propineb, a loss of effect was evident at higher concentrations (100 nM), and the effect was Ca(2+)-independent. Disulfiram, a related dithiocarbamate not coordinated with Zn(2+), also depolymerized actin, suggesting the involvement of the organic structure of dithiocarbamates rather than the leakage of Zn(2+). Nevertheless, propineb did not depolymerize actin in a cell-free system. These data suggest that dithiocarbamates, through the activation of intracellular cascade(s), impair cytoskeletal actin. This effect may contribute to affect synaptic vesicles processing resulting in an impaired cholinergic transmission.
Viviani
Barbara
B
Department of Pharmacological Sciences, Laboratory of Toxicology, University of Milan, Italy. barbara.viviani@unimi.it
Bartesaghi
Stefano
S
Binaglia
Marco
M
Corsini
Emanuela
E
Boraso
Mariaserena
M
Grazi
Enrico
E
Galli
Corrado L
CL
Marinovich
Marina
M
D000109:Acetylcholine / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000427:Alcohol Deterrents / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002474:Cell-Free System; D003599:Cytoskeleton / Q000378:metabolism*; D047630:Depsipeptides / Q000633:toxicity; D004221:Disulfiram / Q000494:pharmacology; D005659:Fungicides, Industrial / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D015032:Zinc / Q000378:metabolism; D015038:Zineb / Q000031:analogs & derivatives* / Q000633:toxicity
D000199:Actins; D000427:Alcohol Deterrents; D047630:Depsipeptides; D005659:Fungicides, Industrial; C012509:propineb; C057531:jasplakinolide; D015032:Zinc; D000109:Acetylcholine; D002118:Calcium; D004221:Disulfiram; D015038:Zineb