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The Putative SLC Transporters Mfsd5 and Mfsd11 Are Abundantly Expressed in the Mouse Brain and Have a Potential Role in Energy Homeostasis
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 Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)ORCID iD: 0000-0002-9681-5129
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Molecular Neuropharmacology)
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, e0156912Article in journal (Refereed) Published
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Text
Abstract [en]

Background Solute carriers (SLCs) are membrane bound transporters responsible for the movement of soluble molecules such as amino acids, ions, nucleotides, neurotransmitters and oligopeptides over cellular membranes. At present, there are 395 SLCs identified in humans, where about 40% are still uncharacterized with unknown expression and/or function(s). Here we have studied two uncharacterized atypical SLCs that belong to the Major Facilitator Superfamily Pfam clan, Major facilitator superfamily domain 5 (MFSD5) and Major facilitator superfamily domain 11 (MFSD11). We provide fundamental information about the histology in mice as well as data supporting their disposition to regulate expression levels to keep the energy homeostasis. Results In mice subjected to starvation or high-fat diet, the mRNA expression of Mfsd5 was significantly down-regulated (P<0.001) in food regulatory brain areas whereas Mfsd11 was significantly up-regulated in mice subjected to either starvation (P<0.01) or high-fat diet (P< 0.001). qRT-PCR analysis on wild type tissues demonstrated that both Mfsd5 and Mfsd11 have a wide central and peripheral mRNA distribution, and immunohistochemistry was utilized to display the abundant protein expression in the mouse embryo and the adult mouse brain. Both proteins are expressed in excitatory and inhibitory neurons, but not in astrocytes. Conclusions Mfsd5 and Mfsd11 are both affected by altered energy homeostasis, suggesting plausible involvement in the energy regulation. Moreover, the first histological mapping of MFSD5 and MFSD11 shows ubiquitous expression in the periphery and the central nervous system of mice, where the proteins are expressed in excitatory and inhibitory mouse brain neurons.

Place, publisher, year, edition, pages
2016. Vol. 11, no 6, e0156912
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-299580DOI: 10.1371/journal.pone.0156912ISI: 000377561000047PubMedID: 27272503OAI: oai:DiVA.org:uu-299580DiVA: diva2:949721
Funder
Swedish Research CouncilThe Swedish Brain FoundationNovo Nordisk
Available from: 2016-07-22 Created: 2016-07-22 Last updated: 2017-11-28Bibliographically approved
In thesis
1. Atypical Solute Carriers: Identification, evolutionary conservation, structure and histology of novel membrane-bound transporters
Open this publication in new window or tab >>Atypical Solute Carriers: Identification, evolutionary conservation, structure and histology of novel membrane-bound transporters
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Solute carriers (SLCs) constitute the largest family of membrane-bound transporter proteins in humans, and they convey transport of nutrients, ions, drugs and waste over cellular membranes via facilitative diffusion, co-transport or exchange. Several SLCs are associated with diseases and their location in membranes and specific substrate transport makes them excellent as drug targets. However, as 30 % of the 430 identified SLCs are still orphans, there are yet numerous opportunities to explain diseases and discover potential drug targets. Among the novel proteins are 29 atypical SLCs of major facilitator superfamily (MFS) type. These share evolutionary history with the remaining SLCs, but are orphans regarding expression, structure and/or function. They are not classified into any of the existing 52 SLC families. The overall aim in this thesis was to study the atypical SLCs with a focus on their phylogenetic clustering, evolutionary conservation, structure, protein expression in mouse brains and if and how their gene expressions were affected upon changed food intake. In Papers I-III, the focus was on specific proteins, MFSD5 and MFSD11 (Paper I), MFSD1 and MFSD3 (Paper II), and MFSD4A and MFSD9 (Paper III). They all shared neuronal expression, and their transcription levels were altered in several brain areas after subjecting mice to food deprivation or a high-fat diet. In Paper IV, the 29 atypical SLCs of MFS type were examined. They were divided into 15 families, based on phylogenetic analyses and sequence identities, to facilitate functional studies. Their sequence relationships with other SLCs were also established. Some of the proteins were found to be well conserved with orthologues down to nematodes and insects, whereas others emerged at first in vertebrates. The atypical SLCs of MFS type were predicted to have the common MFS structure, composed of 12 transmembrane segments. With single-cell RNA sequencing and in situ proximity ligation assay, co-expression of atypical SLCs was analysed to get a comprehensive understanding of how membrane-bound transporters interact.

 

In conclusion, the atypical SLCs of MFS type are suggested to be novel SLC transporters, involved in maintaining nutrient homeostasis through substrate transport.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1346
Keyword
Major facilitator superfamily, solute carrier, transporter, protein expression, mRNA expression, phylogenetic clustering, orthologues, co-expression, subcellular location, nutrition.
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-324206 (URN)978-91-513-0015-3 (ISBN)
Public defence
2017-09-22, B22, BMC, Husargatan 3, Uppsala, 10:15 (English)
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Supervisors
Available from: 2017-08-31 Created: 2017-08-01 Last updated: 2017-09-08

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Perland, EmelieLekholm, EmiliaEriksson, Mikaela M.Bagchi, SonchitaFredriksson, Robert

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