Proteopedia

Solute carrier family 12


Function

The Solute carrier family 12 consists of 9 members which encode electroneutral cation-coupled chloride cotransporters. NKCCs play a vial role in the regulation of ionic balance. NKCCs utilize the existing Na+ and K+ gradients to move Cl- into or out of cells[1].

  • Solute carrier family 12 member 1 (NKCC 1) is a Na+/K+/Cl- cotransporter playing a major role in concentrating urine and in most of the NaCl resorption.
  • Solute carrier family 12 member 2 (NKCC 2) is a Na+/K+/Cl- cotransporter across membranes, involved in chloride transport, metal ion transport and positive regulation of cell volume.
  • Solute carrier family 12 member 3 (NKCC 3) is a Na+/Cl- cotransporter playing a major role in most of the NaCl resorption in the tubule of kidneys[2].
  • Solute carrier family 12 member 4 (NKCC 4 ) mediates the coupled movement of K+ and Cl- ions across the plasma membrane.
  • Solute carrier family 12 member 5 (NKCC 5) is a K+/Cl- cotransporter maintaining Cl homeostasis in neutrons[3].
  • Solute carrier family 12 member 6 (NKCC 6) is a K+/Cl- cotransporter activated by swelling of the cell.

Disease

Mutations in NKCC 2 cause neurodevelopmental disorder non-syndromic hearing loss[4]. Mutations in NKCC 3 play pathogenic effects in Gitelman syndrome[5]. Polymorphism in NKCC 3 contribute to genetic susceptibility to diabetic nephropathy and essential hypertension[6]. Mutations in NKCC 6 are associated with severe sensorimotor neuropathy (ACCPN)[7].

Structural highlights

NKCC 2 cotransports Na+, K+, Cl- in the molar ration of 1:1:2. The 3D structure of NKCC 2 complex with these ions show only K+ and one Cl- ion. [8].


3D structures of solute carrier family 12

Solute carrier family 12 3D structures


Dimer of human solute carrier family 12 member 2 complex with K+ (purple) and Cl- (green) ions (PDB code 7mxo)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Yang X, Wang Q, Cao E. Structure of the human cation-chloride cotransporter NKCC1 determined by single-particle electron cryo-microscopy. Nat Commun. 2020 Feb 21;11(1):1016. doi: 10.1038/s41467-020-14790-3. PMID:32081947 doi:http://dx.doi.org/10.1038/s41467-020-14790-3
  2. ↑ Li N, Gu HF. Genetic and Biological Effects of SLC12A3, a Sodium-Chloride Cotransporter, in Gitelman Syndrome and Diabetic Kidney Disease. Front Genet. 2022 May 3;13:799224. PMID:35591852 doi:10.3389/fgene.2022.799224
  3. ↑ Liu JY, Dai YB, Li X, Cao K, Xie D, Tong ZT, Long Z, Xiao H, Chen MK, Ye YL, Liu B, Tan J, Tang J, Xu ZZ, Gan Y, Zhou YH, Deng F, He LY. Solute carrier family 12 member 5 promotes tumor invasion/metastasis of bladder urothelial carcinoma by enhancing NF-κB/MMP-7 signaling pathway. Cell Death Dis. 2017 Mar 23;8(3):e2691. PMID:28333147 doi:10.1038/cddis.2017.118
  4. ↑ Li N, Gu HF. Genetic and Biological Effects of SLC12A3, a Sodium-Chloride Cotransporter, in Gitelman Syndrome and Diabetic Kidney Disease. Front Genet. 2022 May 3;13:799224. PMID:35591852 doi:10.3389/fgene.2022.799224
  5. ↑ . Correction to: SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. Brain. 2023 Apr 19;146(4):e26. PMID:36670515 doi:10.1093/brain/awad012
  6. ↑ Kim JH, Shin HD, Park BL, Moon MK, Cho YM, Hwang YH, Oh KW, Kim SY, Lee HK, Ahn C, Park KS. SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) polymorphisms are associated with end-stage renal disease in diabetic nephropathy. Diabetes. 2006 Mar;55(3):843-8. PMID:16505253 doi:10.2337/diabetes.55.03.06.db05-1013
  7. ↑ Howard HC, Mount DB, Rochefort D, Byun N, Dupré N, Lu J, Fan X, Song L, Rivière JB, Prévost C, Horst J, Simonati A, Lemcke B, Welch R, England R, Zhan FQ, Mercado A, Siesser WB, George AL Jr, McDonald MP, Bouchard JP, Mathieu J, Delpire E, Rouleau GA. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002 Nov;32(3):384-92. PMID:12368912 doi:10.1038/ng1002
  8. ↑ Moseng MA, Su CC, Rios K, Cui M, Lyu M, Glaza P, Klenotic PA, Delpire E, Yu EW. Inhibition mechanism of NKCC1 involves the carboxyl terminus and long-range conformational coupling. Sci Adv. 2022 Oct 28;8(43):eabq0952. PMID:36306358 doi:10.1126/sciadv.abq0952

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