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.
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