Aquaporin Water Channels: From Atomic Structure to Malaria Abstract The aquaporin water channel proteins confer high water permeability to biological membranes. Discovered in human red cells, AQP1 has been thoroughly characterized biophysically, and the atomic structure of AQP1 has been elucidated. Twelve homologous proteins have been identified in humans. These are selectively permeated by water (aquaporins) or water plus glycerol (aquaglyceroporins). The sites of expression predict the clinical phenotypes. Individuals lacking Colton blood group antigens have mutations in the AQP1 gene. When deprived of water, AQP1-null individuals exhibit a defect in urine concentration and a marked reduction in fluid exchange from lung capillaries. AQP1 is expressed in multiple tissues where physiologically important fluid secretion is known to occur including cerebrospinal fluid in brain and aqueous humor in eye. AQP2 is expressed in renal collecting duct principal cells where membrane trafficking is regulated by vasopressin. Mutations in the human AQP2 gene result in nephrogenic diabetes insipidus, but too little AQP2 expression is found in clinical disorders of urinary concentration, such as lithium therapy and bed wetting. Too much AQP2 expression is found in disorders of fluid retention, such as congestive heart failure and pregnancy. AQP0 is expressed in lens fiber cells and mutations result in familial cataracts. AQP5 is expressed in the apical membranes of salivary and lacrimal glands and sweat glands, and mistargetting may occur in some patients with Sjogren’s syndrome. Aquaporins have been implicated in other human clinical disorders such as brain edema, epilepsy, neuromyelitis optica (AQP4), anhidrosis (AQP5) renal tubular acidosis (AQP6). Aquaglyceroporins have been implicated in malaria, skin hydration (AQP3), glucose homeostasis during starvation and protection against arsenic poisoning (AQP7 and AQP9). Aquaporins are known to protect micro-organisms from freezing and osmotic shock. Plant aquaporins are involved in numerous processes including the uptake of water by rootlets and carbon dioxide by leaves. The physiological roles of aquaporin homologs are being pursued by multiple laboratories worldwide.