Molecular features and physiological roles of K⁺-Cl^- cotransporter 4 (KCC4)

A K⁺-Cl^- cotransport system was documented for the first time during the mid-seventies in sheep and goat red blood cells. It was then described as a Na⁺-independent and ouabain-insensitive ion carrier that could be stimulated by cell swelling and N-ethylmaleimide (NEM), a thiol-reacting agent. Twenty years later, this system was found to be dispensed by four different isoforms in animal cells. The first one was identified in the expressed sequence tag (EST) database by Gillen et al. based on the assumption that it would be homologous to the Na⁺-dependent K⁺-Cl^- cotransport system for which the molecular identity had already been uncovered. Not long after, the three other isoforms were once again identified in the EST databank. Among those, KCC4 has generated much interest a few years ago when it was shown to sustain distal renal acidification and hearing development in mouse. As will be seen in this review, many additional roles were ascribed to this isoform, in keeping with its wide distribution in animal species. However, some of them have still not been confirmed through animal models of gene inactivation or overexpression. Along the same line, considerable knowledge has been acquired on the mechanisms by which KCC4 is regulated and the environmental cues to which it is sensitive. Yet, it is inferred to some extent from historical views and extrapolations.