Human dopamine transporter gene variation: Effects of protein coding variants V55A and V382A on expression and uptake activities

Zhicheng Lin, George R. Uhl

Research output: Contribution to journalArticle

Abstract

The human dopamine transporter (DAT, SLC6A3) is an important 15 exon gene for dopamine neurotransmission and dopamine recycling. Common exon 15 variable number tandem repeat variants can be associated with attention deficit/hyperactivity disorder. Rarer single nucleotide polymorphisms produce missense variants including V55A and V382A. We now report studies of the functional influences of these DAT protein-coding variants. In COS cell transient-expression assays, V382A displays about half of the dopamine uptake velocity Vmax and cocaine analog binding Bmax values of wildtype DAT. V382A lowers dopamine's potency in inhibiting cocaine analog binding by six-fold. Cells expressing V382A or mixtures of V382A and wildtype DAT both display reduced plasma membrane and increased perinuclear expression, consistent with dominant effects of V328A on expression. V55A expresses normally but reveals a 1.7-fold-lower Km for dopamine uptake. Individuals with these human DAT protein variants could display altered dopamine systems.

Original languageEnglish (US)
Pages (from-to)159-168
Number of pages10
JournalPharmacogenomics Journal
Volume3
Issue number3
DOIs
Publication statusPublished - 2003
Externally publishedYes

    Fingerprint

Keywords

  • Cocaine affinity
  • Dominant negative
  • Dopamine transporter (DAT)
  • Dopamine uptake
  • Human variants
  • Intracellular expression

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine
  • Genetics

Cite this