SLC12A3 Membrane Protein Introduction

 Introduction of SLC12A3

Solute carrier family 12 member 3 (also known as Na⁺-Cl^- cotransporter, NCC or NCCT, or as the thiazide-sensitive Na⁺-Cl^- cotransporter or TSC) is a cotransporter in the kidney with the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the gene SLC12A3 located in 16q13. Once the expression of NCC is restrained, it will result in Gitelman syndrome, an autosomal recessive disease characterized by salt wasting and low blood pressure, hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria. There are over a hundred different mutations in the NCC gene.

Function of SLC12A3 Membrane Protein

As SLC12A3 is a protein existed in the apical membrane of the distal convoluted tubule of the nephron, it faces the lumen of the tubule and is in contact with the tubular fluid. The sodium-chloride symporter acts as a transporter of Na⁺ and Cl^- from the tubular fluid into these cells by using the sodium gradient across the apical membrane of the cells in the distal convoluted tubule. Then the Na⁺ will be pumped out of the cell and comes into the bloodstream by the Na⁺-K⁺ ATPase and the Cl^- leaves the cells through the basolateral chloride channel ClC-Kb. It has been reported that NCC influences this process in two control mechanisms. As NCC has to be at the plasma membrane to function, its activity can be regulated by increasing or decreasing the amount of protein at the plasma membrane. Some NCC modulators may regulate the amount of NCC at the cell surface by inducing the insertion or removal, respectively, of the protein from the plasma membrane. Moreover, many residues of NCC can activate or inhibit NCC uptake of Na+ and Cl−. Other NCC modulators can regulate NCC activity by phosphorylating conserved serine/threonine residues. NCC activity can be inhibited by thiazides.

Fig.1 A model of transport mechanisms in the DCT. (Knoers, 2008)

Application of SLC12A3 Membrane Protein in Literature

1. Roca-Argente L., et al. Novel nonsense mutation in the SLC12A3 gene in a Spanish case of Gitelman syndrome. FEBS J. 2018, pii: S0211-6995(18)30072-9. PubMed ID: 29934036
   
   

   This article suggests that Gitelman syndrome (GS), salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria, is caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC) and is recessively inherited. The author finds that the single nucleotide polymorphism (SNP) detected along the SLC12A3 gene is homozygous with the notion of consanguinity.

2. An C., et al. Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population. Lipids Health Dis. 2018, 17(1):83. PubMed ID: 29661184
   
   

   The results demonstrate the importance of SLC12A3 polymorphisms in individuals' difference about their serum lipid profiles, thereby providing evidence that the genetic variants may contribute to CVD development via modulating person's LDL-C level and blood pressure, in certain contexts.

3. Zhang R., et al. Arg913Gln of SLC12A3 gene promotes development and progression of end-stage renal disease in Chinese type 2 diabetes mellitus. Mol Cell Biochem. 2018, 437(1-2):203-210. PubMed ID: 28744814
   
   

   The findings show that the Arg913Gln variation in SLC12A3 is associated with the risk of increased blood pressure and urinary albumin excretion rate (UAER). Hence, SLC12A3- Arg913Gln variation can be regarded as a promising marker for prediction of the development and progression of diabetic nephropathy(DN)- end-stage renal disease (ESRD) in Chinese T2DM patients undergoing hemodialysis.

4. Tutakhel O.A.Z., et al. Dominant functional role of the novel phosphorylation site S811 in the human renal NaCl cotransporter. FASEB J. 2018, 32(8):4482-4493. PubMed ID: 29547703
   
   

   Their study highlights the dominant-negative effect of NCC_SV on T55 and T60 phosphorylation and NCC activity. The authors reveal a new function of NCC_sv in humans that broadens the understanding of NCC regulation in blood pressure control.

5. Shi J., et al. Association of sodium ion transporter gene polymorphisms with essential hypertension among ethnic Koreans from Mudanjiang. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2018, 35(1):116-120. PubMed ID: 29419876
   
   

   The results concluded that the polymorphisms of rs11643718 locus in SLC12A3 gene is associated with the susceptibility for essential hypertension among ethnic Koreans from Mudanjiang area and can be considered as a predictor for the disease.

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Reference

1. Knoers N V. and Levtchenko E N. (2008). Gitelman syndrome. Orphanet Journal of Rare Diseases. 13(2), 148-154.

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