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SLC10A4 Is a Vesicu...
SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
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- Larhammar, Martin, 1985- (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Klas Kullander
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- Patra, Kalicharan (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Klas Kullander
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- Blunder, Martina (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Klas Kullander
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- Emilsson, Lina (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Klas Kullander
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- Peuckert, Christiane (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Klas Kullander
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- Arvidsson, Emma (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Åsa Wallen-Mackenzie
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- Rönnlund, Daniel (author)
- KTH,Experimentell biomolekylär fysik,Royal Institute of Technology, Stockholm
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- Preobraschenski, Julia (author)
- Max Planck Institute for Biophysical Chemistry, Gottingen
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- Birgner, Carolina (author)
- Uppsala universitet,Institutionen för neurovetenskap
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- Limbach, Christoph (author)
- Uppsala universitet,Genetisk utvecklingsbiologi,Klas Kullander
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- Widengren, Jerker (author)
- Royal Institute of Technology
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- Blom, Hans (author)
- Royal Institute of Technology
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- Jahn, Reinhard (author)
- Department of Neurobiology, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany
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- Wallén-Mackenzie, Åsa (author)
- Uppsala universitet,Genetisk utvecklingsbiologi
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- Kullander, Klas (author)
- Uppsala universitet,Genetisk utvecklingsbiologi
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(creator_code:org_t)
- Elsevier BV, 2015
- 2015
- English.
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In: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 77:6, s. 526-536
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- BackgroundThe 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.MethodsWe used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.ResultsWe 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.ConclusionsOur 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Neurologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Neurology (hsv//eng)
Keyword
- Acetylcholine
- amphetamine
- central nervous system
- cocaine
- noradrenaline
- serotonin
- synaptic transmission
- transmitter
- Neuroscience
- Neurovetenskap
Publication and Content Type
- ref (subject category)
- art (subject category)
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Larhammar, Marti ...
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Patra, Kalichara ...
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Blunder, Martina
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Emilsson, Lina
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Peuckert, Christ ...
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Arvidsson, Emma
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Rönnlund, Daniel
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Preobraschenski, ...
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Birgner, Carolin ...
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Limbach, Christo ...
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Widengren, Jerke ...
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Blom, Hans
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Jahn, Reinhard
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Wallén-Mackenzie ...
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Kullander, Klas
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MEDICAL AND HEAL ...
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and Basic Medicine
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MEDICAL AND HEAL ...
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MEDICAL AND HEAL ...
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Biological Psych ...
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Uppsala University
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Royal Institute of Technology