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

In mammalian cells water slowly passes across cell membranes driven by osmotic forces. However, the speed of this process is insufficient for sustained and rapid water fluxes required for an active regulation of water homeostasis, e.g. in the kidney or under conditions of osmotic stress. A novel class of membraneous pore proteins, aquaporins, was detected which facilitates osmotically driven passage of water and, in some instances, small uncharged solutes. So far, ten isoforms of this water channel protein family have been 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 prototypical structural features. The locus of the now obsolete group of mercurial diuretics is pointed out. Further, the general pattern of the tissue-specific aquaporin isoform expression is illustrated, among others in the kidney, eye, inner ear and lung. In more detail we present how particular aquaporin isoforms in the kidney are involved in the regulation of urinary osmolality. Genetic defects in aquaporin-2 are known to result in nephrogenic diabetes insipidus. Further, we point out a variety of disease states which may 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 outline which questions have to be addressed toward this end, which strategies could be followed and which disease states may benefit most obviously from such a therapeutic approach.