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Interaction of 1-methyl-4-phenylpyridinium ion with human platelets
T D Buckman1, R Chang, M S Sutphin
1Department of Psychiatry and Biobehavioral Sciences Medical School, University of California, Los Angeles 90024.
Abstract:
When uptake of the Parkinson's syndrome inducing neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and its major brain metabolite MPP+ (1-methyl-4-phenylpyridinium ion) by human platelets were compared in platelet rich plasma, a much higher rate was observed for the metabolite. The uptake process was saturable (Km = 6.8 microM; Vmax = 0.064 nmole/min/mg protein) and could be blocked by inhibitors of serotonin uptake. The accumulation of MPP+ by the platelets was accompanied by a decrease in intracellular ATP and an inhibition of mitochondrial state 3 respiration. These findings are consistent with earlier reports of the effect of MPP+ on isolated mitochondria as a potential cytotoxic mechanism, but also demonstrate that the dopamine uptake system is not the only means by which this metabolite can be efficiently transported into cells.
Insights
Human platelets efficiently take up the Parkinson
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Parkinson's syndrome can be induced by the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine).
- MPTP is metabolized to MPP+ (1-methyl-4-phenylpyridinium ion), a compound implicated in neurotoxicity.
Purpose of the Study:
- To compare the uptake rates of MPTP and MPP+ in human platelets.
- To investigate the mechanism and consequences of MPP+ uptake by platelets.
Main Methods:
- Uptake studies in platelet-rich plasma.
- Enzyme kinetic analysis (saturation kinetics).
- Assessment of intracellular ATP levels and mitochondrial respiration.
Main Results:
- Platelets exhibited a significantly higher uptake rate for MPP+ compared to MPTP.
- MPP+ uptake was saturable, with a Km of 6.8 microM and Vmax of 0.064 nmole/min/mg protein.
- MPP+ accumulation led to decreased intracellular ATP and inhibited mitochondrial respiration.
Conclusions:
- Human platelets possess an efficient transport system for MPP+, distinct from the dopamine transporter.
- Platelet MPP+ uptake demonstrates a potential cytotoxic mechanism involving ATP depletion and mitochondrial dysfunction.
- Platelets can serve as a model for studying MPP+ transport and its cellular effects relevant to Parkinson's syndrome.