Family 2.A.30 - The Cation-Chloride Co-Transporter Family       

Family ID: 52639

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 some sequence similarity to members of the APC family (TC #2.A.3), but this sequence similarity is insufficient to establish homology. 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).