WATER CHANNELS AND UREA TRANSPORTERS

SUMMARY 1. It now appears that when water crosses an endothelium which is not fenestrated, or an epithelium with tight junctions, it does so rapidly, and with low energy cost, only if the cell membrane contains an adequate number of specific water channels, encoded by one of at least six different genes. 2. The water channel genes so far cloned encode a series of integral membrane proteins called aquaporins, all of approximately 30kDa (265–282 amino acids), in the unglycosylated state. All but one (AQP3) are specific water channels and all but one (AQP4) are inactivated by mercurial compounds. 3. Aquaporin 0 is the major (60%) intrinsic protein (MIP) of lens fibre cells of the eye. Mutations in this gene are associated with cataract formation in mice. 4. Aquaporin 1, also called CHIP‐28, exists in the membrane as a homotetramer, and is present in red blood cells, the choroid plexus, the proximal tubule and descending limb of the loop of Henle in the kidney as well as in many other sites. Surprisingly, no pathological consequence is known in patients lacking a functional AQP1 gene. 5. Aquaporin 2, also called WCH‐CD, is the water channel of the principal cell of the cortical and medullary collecting duct, and is located in cytoplasmic vesicles unless arginine vasopressin is acting, when it is translocated to the apical membrane by synaptobrevins or vesicle associated membrane protein 2 (VAMP2). Lack of a functional AQP2 gene leads to a rare form of nephrogenic diabetes insipidus. 6. Aquaporins 3, 4, and 5 are located in many tissues—AQP3 and AQP4 being in the basolateral membrane of the renal cortical and medullary principal cell, as well as in the gastrointestinal tract (AQP3) and the brain (AQP4). 7. Four sequences are known for urea transporters HUT11—the urea transporter of the human red cell membrane, and HUT2, rUT2, rbUT2—the arginine vasopressin inducible urea transporters of the human, rat and rabbit kidney. They are specifically permeable to urea, not to water, and are claimed to be inhibited by phloretin. 8. The water channel proteins contain six membrane‐spanning regions, whilst the urea transporters are thought to contain at least 10 membrane spanning segments. 9. Very little work has examined the ontogeny of these proteins, except in the rat, and virtually nothing is known of the expression of these genes in pregnancy or in any disorder of fluid balance in the mother or foetus.