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Dopamine transporter mutants selectively enhance MPP+ transport
S Kitayama1, J B Wang, G R Uhl
1Molecular Neurobiology Branch, National Institute on Drug Abuse, Baltimore, Maryland 21224.
Synapse (New York, N.Y.)
|September 1, 1993
Summary
Researchers identified specific mutations in the dopamine transporter (DAT) that enhance the uptake of 1-methyl-4-phenylpyridinium (MPP+), a neurotoxin modeling Parkinson's disease. This discovery could lead to new therapies targeting neurotoxin accumulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- 1-methyl-4-phenylpyridinium (MPP+) is a neurotoxin used in experimental models of Parkinson's disease.
- The dopamine transporter (DAT) selectively concentrates MPP+ in dopaminergic neurons.
- DAT is also a binding site for cocaine, suggesting overlapping recognition mechanisms.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying MPP+ uptake by DAT.
- To identify specific amino acid residues in DAT involved in selective neurotoxin transport.
- To explore potential therapeutic strategies for blocking neurotoxin accumulation in Parkinsonism.
Main Methods:
- Site-directed mutagenesis of the dopamine transporter (DAT).
- Measurement of dopamine and MPP+ uptake kinetics in mutated DAT.
- Assessment of cocaine analog binding to mutated DAT.
Main Results:
- Mutations in the 7th transmembrane domain of DAT increased MPP+ uptake velocity.
- Mutations in the 11th transmembrane domain of DAT increased MPP+ affinity.
- These mutations had minimal effects on dopamine uptake and cocaine analog binding.
Conclusions:
- Specific DAT residues are selectively involved in neurotoxin uptake.
- This study provides the first example of mutations enhancing selective neurotoxin transport via DAT.
- Findings may inform the development of drugs to block the accumulation of Parkinsonism-inducing neurotoxins.