The mammalian aquaporin water channel family: A promising new drug target

In mammalian cells water slowly passes across cell membranes driven by osmo tic forces. However, the speed of this process is insufficient for sustaine d and rapid water fluxes required for an active regulation of water homeost asis, e.g. in the kidney or under conditions of osmotic stress. A novel cla ss of membraneous pore proteins, aquaporins, was detected which facilitates osmotically driven passage of water and, in some instances, small uncharge d solutes. So far, ten isoforms of this water channel protein family have b een found in mammals alone and more than 100 are known altogether. In this review, the chemical properties of these water pore proteins are summarized such as amino acid sequence similarities and peculiarities and some protot ypical structural features. The locus of the now obsolete group of mercuria l diuretics is pointed out. Further, the general pattern of the tissue-spec ific aquaporin isoform expression is illustrated, among others in the kidne y, eye, inner ear and lung. In more detail we present how particular aquapo rin isoforms in the kidney are involved in the regulation of urinary osmola lity. Genetic defects in aquaporin-2 are known to result in nephrogenic dia betes insipidus. Further, we point out a variety of disease states which ma y be related to a dysregulation of water homeostasis. Aquaporin function is now reasonably accessible to biophysical measurements. This paves the way to develop and assay novel therapeutic agents. In a final section we outlin e which questions have to be addressed toward this end, which strategies co uld be followed and which disease states may benefit most obviously from su ch a therapeutic approach.