Regulation of the serotonin transporter by interacting proteins

Biochem Soc Trans. 2001 Nov;29(Pt 6):722-8. doi: 10.1042/0300-5127:0290722.


The serotonin transporter (SERT) plays a critical role in the maintenance of normal neurotransmission by serotonin [5-hydroxytryptamine (5-HT)]. Recent evidence suggests that SERT and other neurotransmitter transporters are tightly regulated. Activation of protein kinase C results in a decrease in SERT-mediated 5-HT uptake, which is due to an internalization of the transporter. However, to date little is known about the mechanism and proteins involved in the down-regulation of the transporter. One candidate SERT-regulatory protein is the SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) protein, syntaxin 1A (Syn1A), which has recently been implicated in the regulation of ion channels as well as the SERT-related gamma-aminobutyric acid- and glycine-transporters. Using 5-HT uptake assays, confocal microscopy and glutathione S-transferase (GST) pull-down assays we showed that Syn1A also interacts with SERT and alters the subcellular localization of the transporter, resulting in a reduction of 5-HT transport. In addition, we have used the yeast two-hybrid system to search for novel regulatory proteins that interact with the cytoplasmic N-terminal domain of SERT. By screening rat brain cDNA library we have identified six potential SERT-binding proteins. Here we also present progress towards the elucidation of the biological relevance of these proteins and their potential role for the regulation of the serotonin transporter.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antigens, Surface / metabolism
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Membrane Glycoproteins / metabolism*
  • Membrane Glycoproteins / physiology*
  • Membrane Transport Proteins*
  • Microscopy, Fluorescence
  • Nerve Tissue Proteins / metabolism
  • Protein Binding
  • Protein Kinase C / metabolism
  • Protein Transport
  • Serotonin / pharmacology
  • Serotonin Plasma Membrane Transport Proteins
  • Syntaxin 1
  • Transfection
  • Two-Hybrid System Techniques


  • Antigens, Surface
  • Carrier Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC6A4 protein, human
  • STX1A protein, human
  • Serotonin Plasma Membrane Transport Proteins
  • Stx1a protein, rat
  • Syntaxin 1
  • Serotonin
  • Protein Kinase C