Rapid and reversible inhibition of aquaporin-4 by zinc

Aquaporin-4 (AQP4) is the predominant water channel in the brain. Although AQP4 plays an important role in brain water homeostasis, the molecular mechanisms of AQP4 regulation are not fully understood. In this report, we show how Zn²⁺ rapidly and reversibly decreases the water permeability of AQP4 when it is reconstituted into proteoliposomes. Mutagenesis analysis identified Cys178, located in cytoplasmic loop D, as a target residue of ZnCl₂ inhibition. Moreover, treatment with diamide enhanced the inhibitory effects of ZnCl₂. These results suggest that the water permeability of AQP4 may be regulated by dynamic changes in intracellular Zn²⁺ concentration linked to the cellular redox state.