Control of AQP8-dependent H 2 O 2 transport across the plasma membrane: Implications for cell signaling

Triggering of tyrosine kinase receptors activates NADPH-oxidases (NOX) to release H 2 O 2 in the outer leaflet of the plasma membrane. To efficiently reach its cytosolic targets and amplify signaling, H 2 O 2 requires aquaporin-8 (AQP8) or other proteinaceous channels endowed with peroxiporin activity. Particularly during stress conditions, cells can regulate the transport of H 2 O 2 as well as H 2 O through AQP8. Besides limiting the risks of excessive oxidation, reversible gating of AQP8 modulates signal strength and duration. Channel gating is achieved through a two-step mechanism, in which sulphenylation of a conserved cysteine (C53) in the mouth of the AQP8 channel precedes its persulfidation. Cystathionine-β-synthase (CBS) activity is essential for channel blockade and addition of exogenous H 2 S restores inhibition. Thus, CBS is the main source of H 2 S that gates AQP8. Based on molecular modeling and mutagenesis experiments, we propose a mechanism explaining how cells tune H 2 O 2 transport to control signaling and limit oxidative stress.