Abstract
Membrane-bound solute carriers (SLCs) are essential as they maintain several physiological functions, such as nutrient uptake, ion transport and waste removal. The SLC family comprise about 400 transporters, and we have identified two new putative family members, major facilitator superfamily domain containing 1 (MFSD1) and 3 (MFSD3). They cluster phylogenetically with SLCs of MFS type, and both proteins are conserved in chordates, while MFSD1 is also found in fruit fly. Based on homology modelling, we predict 12 transmembrane regions, a common feature for MFS transporters. The genes are expressed in abundance in mice, with specific protein staining along the plasma membrane in neurons. Depriving mouse embryonic primary cortex cells of amino acids resulted in upregulation of Mfsd1, whereas Mfsd3 is unaltered. Furthermore, in vivo, Mfsd1 and Mfsd3 are downregulated in anterior brain sections in mice subjected to starvation, while upregulated specifically in brainstem. Mfsd3 is also attenuated in cerebellum after starvation. In mice raised on high-fat diet, Mfsd1 was specifically downregulated in brainstem and hypothalamus, while Mfsd3 was reduced consistently throughout the brain.
Highlights
Membrane-bound transporters are physiologically important as they keep the homeostasis of soluble molecules within cellular compartments, and it is crucial to study their basic histology and function to understand the human body
Note that SLC29A4 diverged evolutionary from the other SLC29 members, since it clustered with the SLC19 family (Fig. 1a) and was more related to MFSD3, than major facilitator superfamily domain containing 1 (MFSD1)
It is evident that MFSD1 is most closely related to the facilitative nucleoside transporter SLC29 family; while MFSD3 clusters with SLC33, the acetyl-CoA transporter family (Fig. 1b)
Summary
Membrane-bound transporters are physiologically important as they keep the homeostasis of soluble molecules within cellular compartments, and it is crucial to study their basic histology and function to understand the human body. The solute carrier (SLC) superfamily is the largest group of membranebound transporters in human and it includes 395 members, divided in 52 families (Hediger et al 2004). SLCs utilize ATP-independent mechanisms to move nutrients, ions, drugs and waste over lipid membranes, and SLC deficiencies are associated with several human diseases (Hediger et al 2013; Lin et al 2015). SLC proteins are grouped into Pfam clans based on functional domains, where the two largest clans, the major facilitator superfamily (MFS) and the amino acid-polyamine organocation (APC) clan (Hoglund et al 2011), contain more than half of all SLC families. The MFS clan includes 16 SLC families, and all the MFS domain (MFSD)# proteins. We are studying two novel MFSD# proteins, major facilitator superfamily domain containing 1 (MFSD1) and 3 (MFSD3). MFSD2a was recently characterized as an omega 3 fatty acid transporter, located in endothelial cells in the blood-brain barrier in mice (Nguyen et al 2014), MFSD4B is a sugar transporter in rat kidneys (Horiba et al 2003) and human MFSD10
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