Facilitation of acetylcholine signaling by the dithiocarbamate fungicide propineb.
Dithiocarbamates (DTCs) are used mainly in agriculture as pesticides and as alcohol deterrent drugs. Neurological complications as well as movement disorders characterized by plastic rigidity, muscle twitch and paralysis are the prevailing symptoms in chronically exposed animals and humans. We investigated whether propineb interfered with peripheral cholinergic transmission in various isolated model systems. In electrically stimulated longitudinal muscle-myenteric plexus preparations (LMMPs), propineb (0.01-1000 nM) concentration-dependently enhanced the amplitude of both neurogenic twitch contractions and tritiated acetylcholine ([3H]ACh) release. The maximum percent increase was achieved by 10 nM propineb and was 19% and 14%, respectively. The effect on twitch contractions was partially antagonized by hexamethonium, a ganglionic nicotinic receptor blocker. In unstimulated LMMPs, propineb (10 pM, 10 nM, 10 microM) did not affect contractions to applied acetylcholine (ACh; 1 nM-10 microM), a finding indicating that propineb has no anticholinesterase activity. In human neuroblastoma cells (SH-SY5Y), propineb facilitated ACh release evoked by KCl depolarization. The increase in ACh release was not associated with detectable alterations of intracellular Ca2+([Ca2+]i) homeostasis. Binding studies carried out with alpha-bungarotoxin in striated muscle cells (L6) failed to demonstrate any influence of propineb on both affinity and capacity of skeletal muscle nicotinic receptors. In conclusion, propineb was found to interfere with cholinergic transmission in LMMPs and SH-SY5Y cells. In LMMPs, the potentiation of cholinergic transmission is partly dependent on the activation of ganglionic nicotinic receptors. Other targets relevant to cholinergic transmission seem not to be affected by propineb.
Marinovich
Marina
M
Laboratory of Toxicology and Section of Theoretical Pharmacology and Receptor Modeling, Department Pharmacological Sciences, University of Milan, Italy. marina.marinovich@unimi.it
Viviani
Barbara
B
Capra
Valerie
V
Corsini
Emanuela
E
Anselmi
Laura
L
D'Agostino
Gianluigi
G
Di Nucci
Amalia
A
Binaglia
Marco
M
Tonini
Marcello
M
Galli
Corrado L
CL
D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005659:Fungicides, Industrial / Q000494:pharmacology*; D006168:Guinea Pigs; D018738:Hexamethonium / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000294:innervation; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015038:Zineb / Q000031:analogs & derivatives* / Q000494:pharmacology*
D002038:Bungarotoxins; D005659:Fungicides, Industrial; C012509:propineb; D018738:Hexamethonium; D000109:Acetylcholine; D015038:Zineb