Tyrosine-533 of rat dopamine transporter: Involvement in interactions with 1-methyl-4-phenylpyridinium and cocaine

Chieko Mitsuhata, Shigeo Kitayama, Katsuya Morita, David Vandenbergh, George R. Uhl, Toshihiro Dohi

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

To improve our understanding of structure-function relationships for neurotransmitter transporters, we performed site-directed mutagenesis of the rat dopamine transporter (DAT) and assessed the functions of the mutants in transiently-expressing COS cells. Tyrosine-533 of rat DAT lies in the 11th transmembrane region, where the corresponding amino acid of human DAT is phenylalanine. Alanine substitution of tyrosine-533 (Y533A) conferred an increased affinity for 1-methyl-4-phenylpyridinium (MPP+). Phenylalanine substitution of tyrosine-533 (Y533F) increased the velocity of MPP+ uptake but decreased DAT's affinity for MPP+. Cocaine's potency in inhibiting dopamine uptake was unchanged with Y533A, but increased with Y533F. Differences in the uptake kinetics and inhibitory potency of cocaine between rat and human DATs were similar to the differences observed between the wild-type and Y533F mutants DATs. Tyrosine-533 may be important for the DAT function and for species differences in transporter functions, including differential sensitivities to cocaine and 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in humans and rats.

Original languageEnglish (US)
Pages (from-to)84-88
Number of pages5
JournalMolecular Brain Research
Volume56
Issue number1-2
DOIs
StatePublished - May 1 1998

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cellular and Molecular Neuroscience

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