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PAT4 is abundantly expressed in excitatory and inhibitory neurons as well as epithelial cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
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2014 (English)In: Brain Research, ISSN 0006-8993, E-ISSN 1872-6240, Vol. 1557, 12-25 p.Article in journal (Refereed) Published
Abstract [en]

PAT4, the fourth member of the SLC36/proton dependent amino acid transporter (PAT) family, is a high-affinity, low capacity electroneutral transporter of neutral amino acids like proline and tryptophan. It has also been associated with the function of mTORC1, a complex in the mammalian target of rapamycin (mTOR) pathway. We performed in situ hybridization and immunohistological analysis to determine the expression profile of PAT4, as well as an RT-PCR study on tissue from mice exposed to leucine. We performed a phylogenetic analysis to determine the evolutionary origin of PAT4. The in situ hybridization and the immunohistochemistry on mouse brain sections and hypothalamic cells showed abundant PAT4 expression in the mouse brain intracellularly in both inhibitory and excitatory neurons, partially co-localizing with lysosomal markers and epithelial cells lining the ventricles. Its location in epithelial cells around the ventricles indicates a transport of substrates across the blood brain barrier. Phylogenetic analysis showed that PAT4 belongs to an evolutionary old family most likely predating animals, and PAT4 is the oldest member of that family.

Place, publisher, year, edition, pages
2014. Vol. 1557, 12-25 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-220143DOI: 10.1016/j.brainres.2014.02.014ISI: 000334081800002PubMedID: 24530433OAI: oai:DiVA.org:uu-220143DiVA: diva2:704184
Available from: 2014-03-11 Created: 2014-03-11 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Characterization of Centrally Expressed Solute Carriers: Histological and Functional Studies with Transgenic Mice
Open this publication in new window or tab >>Characterization of Centrally Expressed Solute Carriers: Histological and Functional Studies with Transgenic Mice
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
: His
Abstract [en]

The Solute Carrier (SLC) superfamily is the largest group of membrane-bound transporters, currently with 456 transporters in 52 families. Much remains unknown about the tissue distribution and function of many of these transporters. The aim of this thesis was to characterize select SLCs with emphasis on tissue distribution, cellular localization, and function.       In paper I, we studied the leucine transporter B0AT2 (Slc6a15). Localization of B0AT2 and Slc6a15 in mouse brain was determined using in situ hybridization (ISH) and immunohistochemistry (IHC), localizing it to neurons, epithelial cells, and astrocytes. Furthermore, we observed a lower reduction of food intake in Slc6a15 knockout mice (KO) upon intraperitoneal injections with leucine, suggesting B0AT2 is involved in mediating the anorexigenic effects of leucine.     In paper II, we studied the postnatal, forebrain-specific deletion of Slcz1, belonging to the SLC18 family, in conditional KO mice (cKO). We observed a decreased response to diazepam and a higher neuronal activity in cortex and hippocampus of cKO mice, as well as an impairment in short-term recognition memory. Intracellular expression was found in neurons but not astrocytes with IHC, indicating SLCZ1 is implicated in neuronal regulation of locomotion and memory.    In paper III, we performed the first detailed histological analysis of PAT4, a transporter belonging to the SLC36 family, involved in the activation of mTOR complex 1 on lysosomes. We found abundant Slc36a4 mRNA and PAT4 expression in mouse brain, using ISH and IHC. We used IHC to localize PAT4 to both inhibitory and excitatory neurons and epithelial cells. We also found both intracellular- and plasmalemmal expression and partial colocalization of PAT4 with lysosomal markers.    Lastly, in paper IV, we provided the first tissue mapping of orphan transporter MCT14 (SLC16A14). Using qPCR, we detected moderate to high Slc16a14 mRNA in the central nervous system and kidney. We found widespread Slc16a14 and MCT14 in mouse brain using ISH and IHC. We also found MCT14 to have intracellular and plasmalemmal expression in mainly excitatory but also inhibitory neurons, as well as epithelial cells. We found MCT14 to be most closely related to MCT8, MCT2 and MCT9, suggesting a similar role for this transporter.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1215
Keyword
SLC, Solute carriers, Amino acid transporter, PAT, B0AT2, mTORC1
National Category
Neurosciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-282956 (URN)978-91-554-9555-8 (ISBN)
Public defence
2016-06-03, B:21, Husargatan. 75124 Uppsala, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2016-05-12 Created: 2016-04-08 Last updated: 2016-06-01

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Roshanbin, SaharHellsten, Sofie VRaine, AmandaFredriksson, Robert

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