Dithiocarbamate propineb induces acetylcholine release through cytoskeletal actin depolymerization in PC12 cells

Area of Science:

• Neuroscience
• Toxicology
• Cell Biology

Background:

• Chronic exposure to dithiocarbamates can cause neurological complications and movement disorders in humans and animals.
• Understanding the molecular mechanisms underlying these effects is crucial for assessing dithiocarbamate toxicity.

Purpose of the Study:

• To investigate the effect of propineb on acetylcholine (Ach) release in rat pheochromocytoma (PC12) cells.
• To elucidate the molecular mechanisms, particularly the role of calcium and actin, involved in propineb-induced Ach release.

Main Methods:

• Differentiated PC12 cells were exposed to varying concentrations of propineb (0.001-100 nM).
• Acetylcholine release was measured.
• Experiments involving calcium chelation and the actin stabilizer jasplakinolide were conducted.
• Actin depolymerization was assessed via microscopy.
• Disulfiram was used to differentiate propineb's effects from zinc-related mechanisms.

Main Results:

• Propineb dose-dependently increased Ach release, with maximal effect at 0.1-1 nM.
• Higher propineb concentrations (10-100 nM) reduced this effect.
• The propineb-induced Ach release was independent of extracellular and intracellular calcium.
• Propineb-induced Ach release was prevented by jasplakinolide, indicating actin involvement.
• Propineb caused actin depolymerization in differentiated PC12 cells, an effect not observed in a cell-free system.
• Disulfiram also depolymerized actin, suggesting the organic structure of dithiocarbamates is key.

Conclusions:

• Propineb impairs cholinergic transmission by activating intracellular cascades that disrupt cytoskeletal actin.
• This actin disruption may affect synaptic vesicle processing, contributing to neurological symptoms associated with dithiocarbamate exposure.
• The mechanism involves the organic dithiocarbamate structure, not zinc leakage.