| 2.A.30 The Cation-Chloride Cotransporter (CCC) Family
Members of the CCC family, found in animals, plants, fungi and bacteria, can catalyze NaCl/KCl symport, NaCl symport, or KCl symport depending on the system. The NaCl/KCl symporters are specifically inhibited by bumetanide while the NaCl symporters are specifically inhibited by thiazide. Most characterized CCC family proteins are from higher animals, but one has been partially characterized from Nicotiana tabacum (a plant), and homologous ORFs have been sequenced from Caenorhabditis elegans (worm), Saccharomyces cerevisiae (yeast) and Synechococcus sp. (blue green bacterium). The latter proteins are of unknown function. These proteins show sequence similarity to members of the APC family (TC #2.A.3). CCC family proteins are usually large (between 1000 and 1200 amino acyl residues), and possess 12 putative transmembrane spanners flanked by large N-terminal and C-terminal hydrophilic domains.
Each of the major types of CCC family members in mammals exist as paralogous isoforms. These may differ in substrates transported. For example, of the four currently recognized KCl transporters, KCC1 and KCC4 both recognize KCl with similar affinities, but KCC1 exhibits anion selectivity: Cl- > SCN- = Br- > PO4-3 > I-, while KCl4 exhibits anion selectivity: Cl- > Br- > PO4-3 = I- > SCN-. Both are activated by cell swelling under hypotonic conditions (Mercado et al., 2000).
One member of the CCC family, the thiazide-sensitive NaCl cotransporter (NCC) of man is involved in 5% of the filtered load of NaCl in the kidney. Mutations in NCC cause the recessive Gitelman syndrome. NCC is a dimer in the membrane (de Jong et al., 2003).
The generalized transport reaction for CCC family symporters is:
{Na+ + K+ + 2Cl-} (out)  {Na+ + K+ + 2Cl-} (in).
That for the NaCl and KCl symporters is:
{Na+ or K+ + Cl-} (out) {Na+ or K+ + Cl-} (in).
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This family belongs to the APC Superfamily.
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| References: |
Boettger, T., M.B. Rust, H. Maier, T. Seidenbecher, M. Schweizer, D.J. Keating, J. Faulhaber, H. Ehmke, C. Pfeffer, O. Scheel, B. Lemcke, J. Horst, R. Leuwer, H.-C. Pape, H. Völkl, C.A. Hübner, and T.J. Jentsch. (2003). Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J. 22: 5422-5434.
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de Jong, J.C., P.H.G.M. Willems, F.J.M. Mooren, L.P.W.J. van den Heuvel, N.V.A.M. Knoers, and R.J.M. Bindels. (2003). The structural unit of the thiazide-sensitive NaCl cotransporter is a homodimer. J. Biol. Chem. 278: 24302-24307.
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Haas, M. and B. Forbush, III. (2000). The Na-K-Cl cotransporter of secretory epithelia. Annu. Rev. Physiol. 62: 515-534.
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Mercado, A., L. Song, N. Vázquez, D.B. Mount, and G. Gamba. (2000). Functional comparison of the K+-Cl- cotransporters KCC1 and KCC4. J. Biol. Chem. 275: 30326-30334.
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Mount, D.B., A. Mercado, L. Song, J. Xu, A.L. George, Jr., E. Delpire, and G. Gamba. (1999). Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family. J. Biol. Chem. 274: 16355-16362.
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Mount, D.B., R.S. Hoover, and S.C. Hebert. (1997). The molecular physiology of electroneutral cation-chloride cotransport. J. Membr. Biol. 158: 177-186.
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Park, J.H. and M.H. Saier, Jr. (1996). Phylogenetic, structural and functional characteristics of the Na-K-Cl cotransporter family. J. Membr. Biol. 149: 161-168.
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Russell, J.M. (2000). Sodium-potassium-chloride cotransport. Physiol. Rev. 80: 211-276.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 2.A.30.1.1 | NaCl/KCl symporter | Animals | NaCl/KCl cotransporter of Rattus norvegicus |
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| 2.A.30.2.1 | Possible NaCl/KCl symporter | Animals | NaCl/KCl cotransporter of Manduca sexta |
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| 2.A.30.3.1 | NaCl/KCl symporter (basolateral) | Animals | NaCl/KCl cotransporter of Homo sapiens |
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| 2.A.30.3.2 | NaCl/KCl symporter | Animals | NaCl/KCl symporter of Squalus acanthias (Shark) |
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| 2.A.30.4.1 | NaCl symporter | Animals | NaCl cotransporter of Rattus norvegicus |
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| 2.A.30.4.2 | Electroneutral NaCl symporter (Gitelman syndrome transporter) | Animals | NaCl symporter of Homo sapiens (1021 aas; CAA62613) |
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| 2.A.30.5.1 | KCl symporter, KCC1 | Animals | KCl cotransporter KCC1 of Rattus norvegicus |
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| 2.A.30.5.2 | KCl symporter KCC2 | Animals | KCl cotransporter KCC2 of Rattus norvegicus |
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| 2.A.30.5.3 | KCl symporter, KCC3 (Andermann Syndrome protein) | Animals | KCl cotransporter KCC3 of Homo sapiens (NP_005126) |
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| 2.A.30.6.1 | Possible NaCl/KCl or KCl symporter, Axi4 | Plants | Axi4 of Nicotiana tabacum |
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