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Gene Review

SLC12A7  -  solute carrier family 12...

Homo sapiens

Synonyms: DKFZP434F076, Electroneutral potassium-chloride cotransporter 4, K-Cl cotransporter 4, KCC4, Solute carrier family 12 member 7
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Disease relevance of SLC12A7


High impact information on SLC12A7

  • Substitution of this region in KCC2 with the equivalent sequence of KCC4 resulted in a chimeric KCC that was devoid of isotonic activity, with intact swelling-activated transport [3].
  • We report a functional comparison in Xenopus oocytes of KCC1 and KCC4, widely expressed representatives of these two subgroups [4].
  • KCC1 and KCC4 exhibit differential sensitivity to transport inhibitors, such that KCC4 is much less sensitive to bumetanide and furosemide [4].
  • KCC4 is also uniquely sensitive to 10 mm barium and to 2 mm trichlormethiazide [4].
  • We have cloned cDNAs encoding mouse KCC3, human KCC3, and human KCC4, three new members of this gene family [5].

Biological context of SLC12A7

  • The human KCC3 and KCC4 genes are located on chromosomes 5p15 and 15q14, respectively [5].
  • Initial and steady state kinetics of hKCC2-injected oocytes were performed in both isotonic and hypotonic conditions, revealing K(m)s for K(+) and Cl(-) of 9.3+/-1.8 mM and 6.8+/-0.9 mM, respectively; both affinities are significantly higher than KCC1 and KCC4 [6].
  • Finally, both KCC3 and KCC4 are crucial for proximal tubular cell volume regulation [1].
  • Consistently, MCF-7 cells obtained advantage in cell proliferation and invasiveness by overexpression of KCC3 and KCC4, respectively [2].
  • A canonical tyrosine phosphorylation site is located in the carboxy termini of KCC2 (R1081-Y1087) and KCC4, but not in other KCC isoforms [7].

Anatomical context of SLC12A7

  • In addition, we used the polymerase chain reaction to demonstrate the presence of KCC1-KCC4 mRNA in the osteoblast-like cell line [8].
  • Thus, KCC4 is expressed on the apical membrane of the choroid plexus, where it likely participates to K(+) reabsorption [9].
  • All other brain structures, e.g. cortex, hippocampus, cerebellum showed no KCC4 immunoreactivity, suggesting very low or absent expression of the cotransporter in these regions [9].
  • In the embryonic brain, KCC4 mRNA is found in the periventricular zone, cranial nerves and choroid plexus [Eur J Neurosci 16 (2002) 2358] [9].
  • Within the brain, the cerebral cortex, hippocampus, and cerebellum revealed minimal KCC4 expression, whereas midbrain and brainstem demonstrated higher levels [9].

Associations of SLC12A7 with chemical compounds

  • Localization of the KCC4 potassium-chloride cotransporter in the nervous system [9].
  • We postulate that KCC4 mediates potassium and chloride exit from the cell and may play an important role in salt absorption by the distal convoluted tubule [10].

Other interactions of SLC12A7

  • Although widely expressed, KCC3 transcripts are the most abundant in heart and kidney, and KCC4 is expressed in muscle, brain, lung, heart, and kidney [5].

Analytical, diagnostic and therapeutic context of SLC12A7

  • Of these three isoforms, only SLC12A7 (KCC4) was detected in murine sperm protein by Western blotting [11].
  • Of the four KCC genes known to encode the respective proteins and their spliced variants, RT-PCR with both rat and human primers revealed the predicted cDNA fragments of KCC1, KCC3a, KCC3b, and KCC4 but not KCC2 in both HLE-B3 cells and in human lens tissue extracts from cataractous patients [12].


  1. Chloride transport in the kidney: lessons from human disease and knockout mice. Jentsch, T.J. J. Am. Soc. Nephrol. (2005) [Pubmed]
  2. IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness. Hsu, Y.M., Chou, C.Y., Chen, H.H., Lee, W.Y., Chen, Y.F., Lin, P.W., Alper, S.L., Ellory, J.C., Shen, M.R. J. Cell. Physiol. (2007) [Pubmed]
  3. A C-terminal domain in KCC2 confers constitutive K+-Cl- cotransport. Mercado, A., Broumand, V., Zandi-Nejad, K., Enck, A.H., Mount, D.B. J. Biol. Chem. (2006) [Pubmed]
  4. Functional comparison of the K+-Cl- cotransporters KCC1 and KCC4. Mercado, A., Song, L., Vazquez, N., Mount, D.B., Gamba, G. J. Biol. Chem. (2000) [Pubmed]
  5. Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. Mount, D.B., Mercado, A., Song, L., Xu, J., George, A.L., Delpire, E., Gamba, G. J. Biol. Chem. (1999) [Pubmed]
  6. Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. Song, L., Mercado, A., Vázquez, N., Xie, Q., Desai, R., George, A.L., Gamba, G., Mount, D.B. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  7. Dependence of KCC2 K-Cl cotransporter activity on a conserved carboxy terminus tyrosine residue. Strange, K., Singer, T.D., Morrison, R., Delpire, E. Am. J. Physiol., Cell Physiol. (2000) [Pubmed]
  8. Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts. Bräuer, M., Frei, E., Claes, L., Grissmer, S., Jäger, H. Am. J. Physiol., Cell Physiol. (2003) [Pubmed]
  9. Localization of the KCC4 potassium-chloride cotransporter in the nervous system. Karadsheh, M.F., Byun, N., Mount, D.B., Delpire, E. Neuroscience (2004) [Pubmed]
  10. Cloning and localization of KCC4 in rabbit kidney: expression in distal convoluted tubule. Velázquez, H., Silva, T. Am. J. Physiol. Renal Physiol. (2003) [Pubmed]
  11. The role of potassium chloride cotransporters in murine and human sperm volume regulation. Klein, T., Cooper, T.G., Yeung, C.H. Biol. Reprod. (2006) [Pubmed]
  12. KCC isoforms in a human lens epithelial cell line (B3) and lens tissue extracts. Misri, S., Chimote, A.A., Adragna, N.C., Warwar, R., Brown, T.L., Lauf, P.K. Exp. Eye Res. (2006) [Pubmed]
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