AQP6 is an intracellular aquaporin channel with a unique functional profile distinct from classical water-channel aquaporins 1. Unlike most aquaporins, AQP6 exhibits very low water permeability but functions as a pH-gated anion channel with selective permeability for nitrate and chloride ions 2. The molecular mechanism involves pH-dependent allosteric gating: protonation of histidine residues (H184 and H189) under acidic conditions triggers opening of the hydrophobic selectivity filter in the central pore, enabling anion permeation 2. A single amino acid mutation (N63G) significantly reduces this anion conductivity, confirming the selectivity filter's importance 2. AQP6 is expressed across multiple tissues including the kidney and central nervous system 3 4. In renal physiology, AQP6 plays roles in maintaining kidney function, though its precise physiological significance differs from other renal aquaporins 1. In the nervous system, AQP6 is among nine aquaporins expressed in the CNS, participating in water flux regulation 5. Clinically, altered AQP6 expression associates with various pathologies including renal cell carcinoma, epithelial ovarian tumors, and Meniere's disease, where decreased AQP6 expression in malignant tissues suggests potential involvement in tumorigenesis 6 7 3.