Regulation of a γ-Aminobutyric Acid Transporter by Reciprocal Tyrosine and Serine Phosphorylation

Michael W. Quick, Jia Hu, Dan Wang, Huai Yu Zhang

Research output: Contribution to journalArticlepeer-review


A feature of the rat brain γ-aminobutyric acid transporter GAT1, and other members of the neurotransmitter transporter family, is its regulated redistribution between intracellular locations and the plasma membrane. Recent studies have focused upon defining the signaling molecules that facilitate this redistribution. Agents that promote direct tyrosine phosphorylation of GAT1 promote a relative increase in surface GAT1 levels, and this results from a slowing of the transporter internalization rate. Agents that act to increase protein kinase C (PKC) activity promote a relative decrease in surface GAT1 levels; whether this effect is caused by direct transporter phosphorylation is unknown. The opposing actions of tyrosine kinase activity and PKC activity raise the possibility that the subcellular distribution of GAT1 is associated with mutually exclusive transporter phosphorylation events. The present experiments show that GAT1 is phosphorylated on serine residues in a PKC-dependent manner, but this state is only revealed when GAT1 tyrosine phosphorylation is eliminated or greatly reduced. The relative levels of serine phosphorylation and tyrosine phosphorylation are negatively correlated. The amount of serine phosphorylation is regulated by agents that affect tyrosine phosphorylation, and vice versa. In addition, the ability of agents that affect tyrosine kinase activity to regulate GAT1 serine phosphorylation requires a change in its tyrosine phosphorylation state. These data support the ideas that GAT1 can exist in either of two mutually exclusive phosphorylation states and that the relative abundance of these states determines in part the relative subcellular distribution of the transporter.

Original languageEnglish (US)
Pages (from-to)15961-15967
Number of pages7
JournalJournal of Biological Chemistry
Issue number16
StatePublished - Apr 16 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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