Mechanism of 1-methyl-4-phenylpyridinium-induced dopamine release from PC12 cells.
The molecular mechanism of 1-methyl-4-phenylpyridinium (MPP+), a Parkinsonism-inducing neurotoxin, has been studied in PC12 cells. The cells treated with MPP+ (100 microM) induced a rapid increase in phosphorylation of tyrosine residues of several proteins, including synaptophysin, a major 38 kDa synaptic vesicle protein implicated in exocytosis. An accelerated release of dopamine by MPP+ correlated with phosphorylation of synaptophysin. Exposing the cells to MPP+ triggered reactive oxygen species (ROS) generation within 60 min of treatment and the said effect was blocked by mazindol, a dopamine uptake blocker. In addition, pretreatment with 50-100 microM of selegiline, a selective MAO-B inhibitor, significantly suppressed MPP+-mediated ROS generation. These effects of MPP+ result in the generation of ROS, which may be involved in neuronal degeneration seen in Parkinson's disease.
Chagkutip
Jaturaporn
J
Departments of Pharmacology and of Neurosciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, 58202, USA.
Govitrapong
Piyarat
P
Klongpanichpak
Sirirat
S
Ebadi
Manuchair
M
D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D000313:Adrenal Medulla / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D005089:Exocytosis; D008454:Mazindol / Q000494:pharmacology; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species; D012642:Selegiline / Q000494:pharmacology; D016708:Synaptophysin / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D017382:Reactive Oxygen Species; D016708:Synaptophysin; D012642:Selegiline; D014443:Tyrosine; D008454:Mazindol; D015655:1-Methyl-4-phenylpyridinium; D002118:Calcium; D004298:Dopamine