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- Larhammar, Martin, 1985-, et al.
(författare)
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SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
- 2015
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 77:6, s. 526-536
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Juranek, Judyta K., et al.
(författare)
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Coordinated bi-directional trafficking of synaptic vesicle and active zone proteins in peripheral nerves
- 2021
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 559, s. 92-98
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Tidskriftsartikel (refereegranskat)abstract
- Synaptic transmission is mediated by neurotransmitters that are stored in synaptic vesicles (SV) and released at the synaptic active zone (AZ). While in recent years major progress has been made in unraveling the molecular machinery responsible for SV docking, fusion and exocytosis, the mechanisms governing AZ protein and SV trafficking through axons still remain unclear. Here, we performed stop-flow nerve ligation to examine axonal trafficking of endogenous AZ and SV proteins. Rat sciatic nerves were collected 1 h, 3 h and 8 h post ligation and processed for immunohistochemistry and electron microscopy. First, we followed the transport of an integral synaptic vesicle protein, SV2A and a SV-associated protein involved in SV trafficking, Rab3a, and observed that while SV2A accumulated on both sides of ligation, Rab3a was only noticeable in the proximal segment of the ligated nerve indicating that only SV trans-membrane protein SV2A displayed a bi-directional axonal transport. We then demonstrate that multiple AZ proteins accumulate rapidly on either side of the ligation with a timescale similar to that of SV2A. Overall, our data uncovers an unexpected robust bi-directional, coordinated -trafficking of SV and AZ proteins in peripheral nerves. This implies that pathological disruption of axonal trafficking will not only impair trafficking of newly synthesized proteins to the synapse but will also affect retrograde transport, leading to neuronal dysfunction and likely neurodegeneration.
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