Synucleins antagonize endoplasmic reticulum function to modulate dopamine transporter trafficking

PLoS One. 2013 Aug 13;8(8):e70872. doi: 10.1371/journal.pone.0070872. eCollection 2013.

Abstract

Synaptic re-uptake of dopamine is dependent on the dopamine transporter (DAT), which is regulated by its distribution to the cell surface. DAT trafficking is modulated by the Parkinson's disease-linked protein alpha-synuclein, but the contribution of synuclein family members beta-synuclein and gamma-synuclein to DAT trafficking is not known. Here we use SH-SY5Y cells as a model of DAT trafficking to demonstrate that all three synucleins negatively regulate cell surface distribution of DAT. Under these conditions the synucleins limit export of DAT from the endoplasmic reticulum (ER) by impairment of the ER-Golgi transition, leading to accumulation of DAT in this compartment. This mechanism for regulating DAT export indirectly through effects on ER and Golgi function represents a previously unappreciated role for the extended synuclein family that is likely applicable to trafficking of the many proteins that rely on the secretory pathway.

Publication types

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

MeSH terms

  • Brain / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Gene Expression
  • Golgi Apparatus / metabolism
  • Humans
  • Protein Binding
  • Protein Transport
  • Synucleins / metabolism*
  • Transfection

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Synucleins