Aquaporin 2: from its discovery to molecular structure and medical implications.

This review describes the discovery of rat aquaporin 2 AQP2 as a vasopressin-regulated water channel, and subsequent isolation of human AQP2. Regarding the structure and function of AQP2, further structural analysis is necessary to understand the basic properties of individual channel function, for examples, such as possible regulation by gating. The critical importance of AQP2 in the urine concentrating ability is demonstrated by a human disease, nephrogenic diabetes insipidus (NDI), and by gene targeting of AQP2 in mice. AQP2 is regulated by many mechanisms from gene transcription to final protein degradation, and vasopressin-stimulated recycling of AQP2 is important for accumulation of AQP2 at the apical membrane. In AQP2-affected NDI, comparison of genotype (types of mutations and mutated residues) and phenotype (clinical characteristics) provides better understanding of both clinical entity of the disease and molecular mechanisms regulating AQP2. Finally, it has become increasingly clear that AQP2 is greatly involved in many human abnormal water balance disorders that await new therapies and clinical markers.