Dopamine transporter endocytic determinants: carboxy terminal residues critical for basal and PKC-stimulated internalization

Mol Cell Neurosci. 2008 Oct;39(2):211-7. doi: 10.1016/j.mcn.2008.06.011. Epub 2008 Jun 25.


Dopamine (DA) reuptake terminates dopaminergic neurotransmission and is mediated by DA transporters (DATs). Acute protein kinase C (PKC) activation accelerates DAT internalization rates, thereby reducing DAT surface expression. Basal DAT endocytosis and PKC-stimulated DAT functional downregulation rely on residues within the 587-596 region, although whether PKC-induced DAT downregulation reflects transporter endocytosis mechanisms linked to those controlling basal endocytosis rates is unknown. Here, we define residues governing basal and PKC-stimulated DAT endocytosis. Alanine substituting DAT residues 587-590 1) abolished PKC stimulation of DAT endocytosis, and 2) markedly accelerated basal DAT internalization, comparable to that of wildtype DAT during PKC activation. Accelerated basal DAT internalization relied specifically on residues 588-590, which are highly conserved among SLC6 neurotransmitter transporters. Our results support a model whereby residues within the 587-590 stretch may serve as a locus for a PKC-sensitive braking mechanism that tempers basal DAT internalization rates.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine / genetics
  • Animals
  • Biotinylation / methods
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins / chemistry*
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Endocytosis / drug effects*
  • Endocytosis / physiology
  • PC12 Cells
  • Protein Kinase C / pharmacology*
  • Protein Structure, Tertiary / physiology
  • Rats
  • Transfection / methods


  • Dopamine Plasma Membrane Transport Proteins
  • Protein Kinase C
  • Alanine
  • Dopamine