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SLC38A10 deficiency in male mice affect plasma levels of threonine and histidine
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)ORCID iD: 0000-0003-4665-3560
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Solute carriers belong to the biggest group of transporters in the human genome, but more knowledge is needed in order to fully understand their function and possible role as therapeutic targets. SLC38 is a family of amino acid transporters, commonly referred to as SNATs, consisting of 11 members. The tenth member, SLC38A10, is one of the least characterized members and is the focus of this study. By using a knockout mouse model, we studied the biological effects of SLC38A10 deficiency in vivo. We performed a transcriptomic analysis of whole brain and found seven differentially expressed genes in SLC38A10 deficient mice (Gm48159, Nr4a1, Tuba1c, Lrrc56, mt-Tp, Hbb-bt and Snord116/9). By measuring amino acids in plasma, we found lower levels of threonine and histidine in males, while no amino acids were altered in females, suggesting that SLC38A10-/- might affect sexes differently. Using RT-qPCR, we investigated the effect of SLC38A10 deficiency on mRNA expression of other SLC38 members, Mtor and Rps6kb1 in brain, liver, lung, muscle and kidney, but no differences were found. A relative telomere length measurement was also made, as a marker for cellular age, but no differences were found between the genotypes. We conclude that SLC38A10 might be important for keeping amino acid homeostasis in plasma, at least in males, but no major effects were seen on transcriptomic expression or telomere length in whole brain. 

Keywords [en]
Slc38a10, SNAT10, knockout, amino acid homeostasis, gene expression analysis
National Category
Physiology and Anatomy Cell and Molecular Biology Other Basic Medicine
Identifiers
URN: urn:nbn:se:uu:diva-473276OAI: oai:DiVA.org:uu-473276DiVA, id: diva2:1653760
Available from: 2022-04-24 Created: 2022-04-24 Last updated: 2025-02-10
In thesis
1. The Biological Importance of the Amino Acid Transporter SLC38A10: Characterization of a Knockout Mouse
Open this publication in new window or tab >>The Biological Importance of the Amino Acid Transporter SLC38A10: Characterization of a Knockout Mouse
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The biggest group of transporters, the solute carriers (SLCs), has more than 400 members, and about 30% of these are still orphan. In order to decipher their biological function and possible role in disease, there is a need for characterization of these. Around 25% of SLCs are estimated to have amino acids as substrates, including transporters belonging to the SLC38 family. The SLC38 members are sometimes referred to their alternative name: sodium-coupled neutral amino acid transporters (SNATs). One of these transporters, SNAT10 (or SLC38A10), has been characterized as a bidirectional transporter of glutamate, glutamine, alanine and aspartate, as well as having an efflux of serine, and is ubiquitously expressed in the body. However, its biological importance is not yet understood. The aim with this thesis was to characterize a mouse model deficient in SNAT10 protein in order to find the biological importance of this transporter. In paper I, this is done by using a series of behavioral tests, including the open field test, elevated plus maze, rotarod and Y-maze, among others. The SNAT10 knockout mouse was found to have an increased risk-taking behavior, but no motor or spatial working memory impairments. Furthermore, the knockout mouse was found to have a decreased body weight. In paper II, an additional behavioral characterization was performed by using the multivariate concentric square field™ (MCSF) test. The MCSF test is an arena with different zones associated to different behavioral traits, which generates a behavioral profile depending on where the mouse spends its time. The result from this test implies that the SNAT10 deficient mouse has a lower explorative behavior than its wild type littermates. In paper III, gene expression was studied in whole brain and some genes related to cell cycle regulation and p53 expression were found to be differentially expressed in the knockout brain. Additional gene expression was studied in kidney, liver, lung and muscle, but no changes were found. Plasma levels of histidine and threonine were altered in males, but no altered amino acid levels were found in knockout females, suggesting a possible sex-specific effect. These studies together imply that SNAT10 might be involved in processes related to risk-taking and explorative behavior in the open field and MCSF tests. SNAT10 deficiency also affected amino acid levels in plasma, indicating a disrupted amino acid homeostasis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2022. p. 47
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 313
Keywords
Solute carrier, SLC, SNAT10, SLC38A10, phenotyping, behavior, amino acids, knockout mouse model
National Category
Physiology and Anatomy Neurosciences Other Basic Medicine Biochemistry Molecular Biology
Research subject
Pharmaceutical Science
Identifiers
urn:nbn:se:uu:diva-473278 (URN)978-91-513-1515-7 (ISBN)
Public defence
2022-06-10, Room C4:301, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2022-05-19 Created: 2022-04-24 Last updated: 2025-02-20Bibliographically approved

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