SLC5A12 Membrane Protein Introduction

Introduction of SLC5A12

SLC5A12 (solute carrier family 5 member 12), also known as sodium-iodide related cotransporter, or SMCT2, is an about 67.6 kDa transmembrane protein that comprises 618 amino acids length. In humans, it is encoded by the SLC5A12 gene mapped at the chromosome 11p14.2. SLC5A12 has 13 putative transmembrane domains, a cytoplasmic C terminus, an exoplasmic N terminus, 2 putative N-glycosylation sites, and some putative phosphorylation sites. It is a member of the sodium glucose cotransporter (SLC5) gene family which contains 12 human cotransporters. Among them, SLC5A12 is localized to the apical membrane of epithelial cells lining the intestinal tract and proximal tubule. It is also found in the brain and retina, but the expression is restricted to astrocytes and Müller cells.

Function of SLC5A12 Membrane Protein

SLC5A12 has been identified as a low-affinity Na(+)-coupled solute transporter in a Na(+)-dependent manner. Considering that the substrate specificity of this transporter is similar to that of monocarboxylate transporters (MCTs), it is also named sodium-coupled SMCT2. It is served to catalyze the active transport across the plasma membrane of various monocarboxylates such as lactate, pyruvate, propionate, butyrate, nicotinate, and beta-D-hydroxybutyrate, and possibly responsible for the first stage of monocarboxylate reabsorption from the lumen of the proximal tubule of the kidney and small intestine. In SLC5 family, there is a member of high-affinity Na(+)-coupled transporter namely SLC5A8, whose expression pattern along the intestinal tract is opposite to that of SLC5A12. Both can increase the intracellular concentration of monocarboxylate anions that then exchanges with luminal urate through urate-anion exchangers. And the reabsorption of blood lactate (~1.5 mM) is mediated by SLC5A12 in the initial part of the proximal tubule and by SLC5A8 in the distal region of the proximal tubule.

Fig.1 The sodium/iodide symporter (NIS) models and SLC5 family alignment. (Ferrandino, 2016)

Application of SLC5A12 Membrane Protein in Literature

1. Sivaprakasam S., et al. Short-chain fatty acid transporters: role in colonic homeostasis. Compr Physiol. 2017, 8(1): 299-314. PubMed ID: 29357130
   
   

   A number of transport systems operate in cellular uptake of short-chain fatty acid (SCFA). Among them, SMCT1 (SLC5A8) and SMCT2 (SLC5A12) are Na⁺-coupled; SMCT1-mediated transport is electrogenic (Na⁺: SCFA stoichiometry=2: 1) while SMCT2-mediated transport is electroneutral (Na⁺: SCFA stoichiometry=1: 1). Both SMCT1 and SMCT2 are exclusively expressed in the apical membrane.

2. Barat A., et al. Solute carriers (SLCs) identified and characterized from kidney transcriptome of golden mahseer (Tor putitora) (Fam: Cyprinidae). Comp Biochem Physiol B Biochem Mol Biol. 2016, 200: 54-61. PubMed ID: 27287540
   
   

   This paper performs RNA sequencing of kidney tissue of golden mahseer by Illumina platform to identify the solute carrier families and characterize 24 putatively functional genes. In these genes, 11 of them are differentially expressed in different tissues by qRT-PCR and slc5a1, slc5a12, slc12a3, slc13a3, slc22a13 and slc26a6 are showed high expression in kidney.

3. Haas R., et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol. 2015, 13(7): e1002202. PubMed ID: 26181372
   
   

   The results indicate that lactate accumulates in the synovia of rheumatoid arthritis patients and extracellular sodium lactate, and lactic acid can inhibit the motility of CD4⁺ and CD8⁺ T cells, respectively. This selective control of the motility of T cells is mediated by subtype-specific transporters Slc5a12 and Slc16a1 that is found selectively expressed by CD4⁺ and CD8⁺ subsets.

4. Ohkubo M., et al. Nicotinate uptake by two kinetically distinct Na⁺-dependent carrier-mediated transport systems in the rat small intestine. Drug Metab Pharmacokinet. 2012, 27(2): 255-262. PubMed ID: 22123132
   
   

   The results in this study suggest that a high-affinity type of SMCT1-like transporter would be additionally in operation in the ileum, and a low-affinity type of SMCT2-like transporter would be in the operation with high capacity throughout small intestines, playing the role as a major intestinal nicotinate uptake transporter.

5. Teramae H., et al. The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract. Biomed Res. 2010, 31(4): 239-249. PubMed ID: 20834181
   
   

   This review examines the distribution and cellular localization of SMCT2 in the digestive tract of mice by using in situ hybridization technique, immunohistochemistry, and quantitative PCR analysis and compares the expression pattern with other transporters for monocarboxylates.

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Reference

1. Ferrandino G, et al. (2016). Na⁺ coordination at the Na2 site of the Na⁺/I- symporter. Proc Natl Acad Sci U S A. 113(37), E5379-5388.

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