Aquaporin 8 is involved in H2 O2 -mediated differential regulation of metabolic signaling by α1 - and β-adrenoceptors in hepatocytes.

Reactive oxygen species participate in regulating intracellular signaling pathways. Herein, we investigated the reported opposite effects of hydrogen peroxide (H2 O2 ) on metabolic signaling mediated by activated α1 - and β-adrenoceptors (ARs) in hepatocytes. In isolated rat hepatocytes, stimulation of α1 -AR increases H2 O2 production via NADPH oxidase 2 (NOX2) activation. We find that the H2 O2 thus produced is essential for α1 -AR-mediated activation of the classical hepatic glycogenolytic, gluconeogenic, and ureagenic responses. However, H2 O2 inhibits β-AR-mediated activation of these metabolic responses. We show that H2 O2 mediates its effects on α1 -AR and β-AR by permeating cells through aquaporin 8 (AQP8) channels and promoting Ca2+ mobilization. Thus, our findings reveal a novel NOX2-H2 O2 -AQP8-Ca2+ signaling cascade acting downstream of α1 -AR in hepatocytes, which, by negatively regulating β-AR signaling, establishes negative crosstalk between the two pathways.