SLC5A3 Membrane Protein Introduction

Introduction of SLC5A3

SLC5A3, also known as solute carrier family 5 (sodium/Myo-inositol cotransporter) member 3, solute carrier family 5 (inositol transporters) member 3, solute carrier family 5 (Inositol transporter) member 3, SMIT, SMIT1, or BCW2, is a transmembrane protein of 79.7 kDa that contains 718 amino acids. In humans, it is encoded by the SLC5A3 gene which resides on the chromosome 21q22.11. SLC5A3 belongs to the solute carrier family 5 (SLC5A) composed of 11 human members, all with 14 predicted transmembrane domains. SLC5A3 protein is responsible for the transport of sodium and Myo-inositol in response to hypertonic stress. SLC5A3 mRNA has been found in the brain, kidney, lung, pancreas, and placenta tissue, also in the heart and skeletal muscle.

Function of SLC5A3 Membrane Protein

SLC5A3 is a plasma membrane protein in charge of the concentrative accumulation of Myo-inositol in numerous tissues. This protein cotransports sodium and Myo-inositol in a ratio of 2:1, and has the ability to transport many other sugars (e.g. scyllo-inositol, L-fucose, etc.) in Xenopus oocytes. In brain and renal cells, hypertonicity causes an increase in SLC5A3 expression thereby raising the cellular concentration of Myo-inositol. The renal medullary cells show high concentrations of Myo-inositol, betaine, sorbitol, and glycero-phosphocholine. Accumulation of these organic osmolytes helps cells to regulate their osmolarity in response to high extracellular osmolality which occurs in situations, such as concentrating urine. To date, there are other two Myo-inositol transporters have been identified, SLC5A11 (SMIT2) and HMIT. SLC5A11 has similar affinity for sodium and Myo-inositol as SLC5A3, but its activity differs in that it transports D-glucose and chiro-inositol, and cannot be inhibited by L-fructose.

Fig.1 Protein model for human SMIT1 and postulated splice variants. (Schneider, 2015)

Application of SLC5A3 Membrane Protein in Literature

1. Tan M.S., et al. Integrative machine learning analysis of multiple gene expression profiles in cervical cancer. PeerJ. 2018, 6: e5285. PubMed ID: 30065881
   
   

   This study proposed an integrative machine to analyze gene expression profiles in cervical cancer to identify a set of genetic markers. Functional analysis on 21 genes showed significant enrichment in a 9-potential gene expression signature, namely PEG3, SPON1, RPLP2 and BTD (upregulations) and SLC5A3, COPB2, PRDX3, LSM3 and AS1B (downregulations).

2. Edamatsu M., et al. Differential localizations of the Myo-inositol transporters HMIT and SMIT1 in the cochlear stria vascularis. Neurosci Lett. 2018, 674: 88-93. PubMed ID: 29551423
   
   

   These results indicated that HMIT was expressed in basal cells and marginal cells of stria vascularis and SMIT1 expression was enriched in basal cells. The article speculated that HMIT and SMIT1 were likely to play essential roles in the homeostasis of cochlear fluids, for instance, by participating in pH regulation and osmoregulation.

3. Leithner K., et al. TASK-1 regulates apoptosis and proliferation in a subset of non-small cell lung cancers. PLoS One. 2016, 11(6): e0157453. PubMed ID: 27294516
   
   

   Compared with TASK-1, three Na⁺-coupled nutrient transporters, SLC5A3, SLC5A6, and SLC38A1, were found to transport Myo-inositol, biotin, and glutamine, respectively, to be greatly overexpressed in lung adenocarcinomas. It was the first time that the TASK-1 channel modulated apoptosis and proliferation in a subset of non-small cell lung cancer.

4. Szpakowicz A., et al. The rs9982601 polymorphism of the region between the SLC5A3/MRPS6 and KCNE2 genes associated with a prevalence of myocardial infarction and subsequent long-term mortality. Pol Arch Med Wewn. 2017, 125(4): 240-248. PubMed ID: 25697262
   
   

   This review demonstrated that the rs9982601 polymorphism of region between SLC5A3/MRPS6 and KCNE2 genes was correlated with long-term mortality in high-risk patients after myocardial infarction (MI). Furthermore, these findings also supported the previous reports on the relationship of the polymorphism and the prevalence of MI.

5. Andronic J., et al. Hypotonic activation of the Myo-inositol transporter SLC5A3 in HEK293 cells probed by cell volumetry, confocal and super-resolution microscopy. PLoS One. 2015, 10(3): e0119990. PubMed ID: 25756525
   
   

   The article explored SLC5A3 protein as a potential transporter of Myo-inositol in hyponically swollen HEK293 cells and examined the correlation between the hypotonicity-induced outcomes in plasma membrane permeability to Myo-inositol Pino [m/s] and the expression of SLC5A3. These data first provided evidence for swelling-mediated activation of SLC5A3.

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Reference

1. Schneider S. (2015). Inositol transport proteins. FEBS Lett. 589(10), 1049-1058.

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