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Transport of L-glutamine, L-alanine, L-arginine and L-histidine by the neuron-specific Slc38a8 (SNAT8) in CNS
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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2015 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 427, no 6, 1495-1512 p.Article in journal (Refereed) Published
Abstract [en]

Glutamine transporters are important for regulating levels of glutamate and GABA in the brain. To date, six members of the SLC38 family (SNATs) have been characterized and functionally subdivided into System A (SNAT1, SNAT2 and SNAT4) and System N (SNAT3, SNAT5 and SNAT7). Here we present a first functional characterization of SLC38A8, one of the previous orphan transporters from the family and we suggest that the encoded protein should be named SNAT8 to adhere with the SNAT nomenclature. We show that SLC38A8 have preference for transporting L-glutamine, L-alanine, L-arginine, L-histidine, and L-aspartate using a Na(+)-dependent transport mechanism and that the functional characteristics of SNAT8 has highest similarity to the known System A transporters. We also provide a comprehensive CNS expression profile in mouse brain for the Slc38a8 gene and the SNAT8 protein. We show that Slc38a8 (SNAT8) is expressed in all neurons, both excitatory and inhibitory, in mouse brain using in situ hybridization and immunohistochemistry. Furthermore, proximity ligation assay show highly similar subcellular expression of SNAT7 and SNAT8. In conclusion, the neuronal SLC38A8 have a broad amino acid transport profile and is the first identified neuronal System A transporter. This suggests a key role of SNAT8 in the glutamine/glutamate(GABA) cycle in the brain.

Place, publisher, year, edition, pages
2015. Vol. 427, no 6, 1495-1512 p.
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:uu:diva-238741DOI: 10.1016/j.jmb.2014.10.016ISI: 000351798700021PubMedID: 25451601OAI: oai:DiVA.org:uu-238741DiVA: diva2:772064
Available from: 2014-12-16 Created: 2014-12-16 Last updated: 2017-12-05Bibliographically approved
In thesis
1. Characterization of Amino Acid Transporters: Transporters expressed in the central nervous system belonging to the Solute Carrier family SLC38
Open this publication in new window or tab >>Characterization of Amino Acid Transporters: Transporters expressed in the central nervous system belonging to the Solute Carrier family SLC38
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In cells and organelles transporters are responsible for translocation of amino acids, sugars and nucleotides among others. In the central nervous system (CNS), amino acid transporters can function as neurotransmitter transporters and nutrient sensors. The Solute carrier (SLC) superfamily is the largest family of transporters with 395 members divided in 52 families. The system A and system N amino acid transporter family, SLC38, consists of 11 members, SNAT1-11 (SLC38A1-11). The members are expressed in the brain, exclusively in neurons or astrocytes and some in both. Amino acid signaling is mainly regulated via two pathways, the amino acid responsive (AAR) pathway and the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) pathway. These pathways regulate the protein synthesis in opposite directions depending on the amino acid availability. SLC38 members along with other SLCs have been identified to participate in these pathways.

In paper I, the regulation of SLC genes after complete amino acid starvation in mouse hypothalamic cells have been studied with microarray and we found that 47 SLC genes were significantly altered at five hours of starvation. Interestingly, we found that Slc38a1 and Slc38a7 were upregulated along with the known starvation responding gene, Slc38a2. A complementary starvation study for the SLC38 genes was performed using primary mouse embryonic cortex cells. We found that Slc38a1, Slc38a2, Slc38a5, Slc38a6 and Slc38a8 were upregulated while Slc38a3, Slc38a7 and Slc38a11 were downregulated.

Three members from the SLC38 family, SNAT8 (paper IV), SNAT9 (paper III) and SNAT10 (paper II) have been histologically characterized in mouse brain and all these transporters are exclusively neuronal. SNAT8 and SNAT10 were also functionally characterized and shown to be transporters for alanine and glutamine among others. SNAT8 was shown to mediate sodium dependent transport and was classified to system A. SNAT10 was shown to be a sodium independent bidirectional transporter and displayed characteristics for system A and N. SNAT9 is a lysosomal component of the Ragulator-Rag complex which senses amino acid availability and activates mTORC1. In paper III we also found that Slc38a9 gene expression was upregulated following starvation and downregulated following high-fat diet in mouse brain.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1180
Keyword
Solute carriers, amino acid transporter, SLC38 family, SLC38A8, SNAT8, SLC38A10, SNAT10, SLC38A9, SNAT9, amino acid starvation, AAR, mTORC1
National Category
Medical and Health Sciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-275723 (URN)978-91-554-9477-3 (ISBN)
Public defence
2016-04-01, B/A1:107a BMC, Biomedicinskt centrum Husargatan 3, Uppsala, 10:15 (English)
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Available from: 2016-03-11 Created: 2016-02-05 Last updated: 2016-03-17

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Hägglund, Maria G AHellsten, Sofie VBagchi, SonchitaPhilippot, GaëtanSreedharan, SmithaTafreshiha, AtiehFredriksson, Robert

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