title: SLC10A4 is a vesicular amine-associated transporter modulating dopamine homeostasis.
abstract: BACKGROUND
  The neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.
  
  
  METHODS
  We used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.
  
  
  RESULTS
  We show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.
  
  
  CONCLUSIONS
  Our results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Larhammar
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Kalicharan
authors.initials: K
authors.lastname: Patra
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Blunder
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Lina
authors.initials: L
authors.lastname: Emilsson
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Christiane
authors.initials: C
authors.lastname: Peuckert
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Arvidsson
authors.affiliation: Department of Biomolecular Physics, Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rönnlund
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Preobraschenski
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Carolina
authors.initials: C
authors.lastname: Birgner
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Limbach
authors.affiliation: Department of Biomolecular Physics, Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Jerker
authors.initials: J
authors.lastname: Widengren
authors.affiliation: Department of Biomolecular Physics, Applied Physics, Royal Institute of Technology, Stockholm, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Blom
authors.affiliation: Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Jahn
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Wallén-Mackenzie
authors.affiliation: Department of Neuroscience, Uppsala University, Uppsala, Sweden.. Electronic address: klas.kullander@neuro.uu.se.
authors.forename: Klas
authors.initials: K
authors.lastname: Kullander
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D006706:Homeostasis / Q000502:physiology*; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D027981:Symporters; D013572:Synaptic Vesicles / Q000378:metabolism; D014191:Tranylcypromine / Q000494:pharmacology; D050494:Vesicular Acetylcholine Transport Proteins / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018765:Dopamine Uptake Inhibitors; D008996:Monoamine Oxidase Inhibitors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C000601541:SLC10A4 protein, mouse; C493453:Slc18a2 protein, mouse; C493460:Slc18a3 protein, mouse; D027981:Symporters; D050494:Vesicular Acetylcholine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D033921:Vesicular Transport Proteins; D012701:Serotonin; D014191:Tranylcypromine; D000661:Amphetamine; D004298:Dopamine; D009638:Norepinephrine
keywords: Acetylcholine; Amphetamine; Central nervous system; Cocaine; Noradrenaline; Serotonin; Synaptic transmission; Transmitter