Molecular physiology of cation-coupled Cl- cotransport:: the SLC12 family

The electroneutral cation-chloride-coupled cotransporter gene family (SLC12) was identified initially at the molecular level in fish and then in mammals. This nine-member gene family encompasses two major branches, one including two bumetanide-sensitive Na+-K+-2Cl(-) cotransporters and the thiazide-sensitive Na+:Cl- cotransporter. Two of the genes in this branch (SLC12A1 and SLC12A3), exhibit kidney-specific expression and function in renal salt reabsorption, whereas the third gene (SLC12A2) is expressed ubiquitously and plays a key role in epithelial salt secretion and cell volume regulation. The functional characterization of both alternatively-spliced mammalian Na+-K+-2Cl(-) cotransporter isoforms and orthologs from distantly related species has generated important structure-function data. The second branch includes four genes (SLC12A4-7) encoding electroneutral K+-Cl- cotransporters. The relative expression level of the neuron-specific SLC12A5 and the Na+-K+-2Cl(-) cotransporter SLC12A2 appears to determine whether neurons respond to GABA with a depolarizing, excitatory response or with a hyperpolarizing, inhibitory response. The four K+-Cl- cotransporter genes are co-expressed to varying degrees in most tissues, with further roles in cell volume regulation, transepithelial salt transport, hearing, and function of the peripheral nervous system. The transported substrates of the remaining two SLC12 family members, SLC12A8 and SLC12A9, are as yet unknown. Inactivating mutations in three members of the SLC12 gene family result in Mendelian disease; Bartter syndrome type I in the case of SLC12A1, Gitelman syndrome for SLC12A3, and peripheral neuropathy in the case of SLC12A6. In addition, knockout mice for many members of this family have generated important new information regarding their respective physiological roles.