aquaporin

Aquaporins are a family of integral membrane proteins arranged as tetramers, each monomer forming an hourglass-shaped pore that permits bidirectional water flow while excluding ions and most solutes (some, like AQP3, also permit glycerol - 'aquaglyceroporins'). At least 13 mammalian isoforms (AQP0-12) exist with tissue-specific distribution: AQP1 in proximal tubule/thin descending limb/RBCs (constitutively active, mediates baseline water reabsorption), AQP2 in the principal cells of the renal collecting duct (apical membrane, ADH-regulated), AQP3 and AQP4 in the basolateral membrane of collecting duct cells (constitutive exit pathway), AQP0 in lens fiber cells (mutations cause congenital cataracts), and AQP5 in salivary/lacrimal glands.

Clinical significance centers on AQP2: ADH binds V2 receptors on the basolateral membrane of collecting duct principal cells, activating Gs-adenylate cyclase-cAMP-PKA signaling, which triggers phosphorylation and trafficking of AQP2 from intracellular vesicles to the apical membrane, increasing water permeability and reabsorption. Long-term ADH exposure also upregulates AQP2 gene transcription. This mechanism explains urine concentrating ability and is the basis of central and nephrogenic diabetes insipidus (DI): central DI results from deficient ADH secretion (e.g., pituitary/hypothalamic damage), while nephrogenic DI results from renal resistance to ADH, often due to mutations in the AQP2 gene or the V2 receptor (X-linked, or acquired from lithium toxicity, hypercalcemia, or hypokalemia, which impair AQP2 trafficking/expression). Desmopressin (DDAVP), a V2 agonist, is used to distinguish central from nephrogenic DI (water deprivation test) and to treat central DI. Additionally, syndrome of inappropriate ADH secretion (SIADH) involves excessive AQP2 insertion leading to water retention and hyponatremia. Aquaporins are also relevant in cerebral edema (AQP4 in astrocytes) and are targets of autoimmune attack in neuromyelitis optica (anti-AQP4 antibodies), a demyelinating disease distinct from MS.