Aquaporin 8 is involved in H 2 O 2 -mediated differential regulation of metabolic signaling by α 1 - and β-adrenoceptors in hepatocytes

• Published in: FEBS letters Vol. 594; no. 10; pp. 1564 - 1576
• Main Authors: Vilchis-Landeros, Magdalena, Guinzberg, Raquel, Riveros-Rosas, Héctor, Villalobos-Molina, Rafael, Piña, Enrique
• Format: Journal Article
• Language: English
• Published: England 01.05.2020
• Subjects: Animals; Aquaporins - metabolism; Calcium Signaling; Gluconeogenesis; Glycogenolysis; Hepatocytes - metabolism; Humans; Hydrogen Peroxide - metabolism; Male; NADPH Oxidase 2 - metabolism; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Adrenergic, beta - metabolism; Signal Transduction; signaling; adrenaline; glycogenolysis; Ca2+ mobilization; α1-adrenergic receptors; epinephrine; ureagenesis; H2O2; gluconeogenesis; β-adrenergic receptors; hepatocytes
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1002/1873-3468.13763

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