Electroneutral Cation-Chloride Cotransporters in the Central Nervous System

Several members of the cation-chloride cotransporter (solute carrier family 12, SLC12) gene family are expressed within the central nervous system, with one family member, the K+-Cl- cotransporter KCC2, exclusive to neurons. These transporters are best known for their roles in cell volume regulation and epithelial salt transport, but are increasingly receiving attention in neuroscience. In particular, intracellular chloride activity and hence the neuronal response to GABA and glycine appears to be determined by a balance between chloride efflux and influx through KCC2 and the Na+-K+-2Cl- cotransporter NKCC1, respectively. This relationship has important implications for neuronal development, sensory perception, neuronal excitability, and the response to neuronal injury. Finally, the association between loss of function in the K+-Cl- cotransporter KCC3, with a severe peripheral neuropathy associated with agenesis of the corpus callosum, has revealed an unexpected role for K+-Cl- cotransport in the development and/or maintenance of both the central and peripheral nervous systems.