NOX2 activated by α1-adrenoceptors modulates hepatic metabolic routes stimulated by β-adrenoceptors.

Abstract:

:The NADPH oxidase (NOX) family of enzymes oxidase catalyzes the transport of electrons from NADPH to molecular oxygen and generates O(2)(•-), which is rapidly converted into H(2)O(2). We aimed to identify in hepatocytes the protein NOX complex responsible for H(2)O(2) synthesis after α(1)-adrenoceptor (α(1)-AR) stimulation, its activation mechanism, and to explore H(2)O(2) as a potential modulator of hepatic metabolic routes, gluconeogenesis, and ureagenesis, stimulated by the ARs. The dormant NOX2 complex present in hepatocyte plasma membrane (HPM) contains gp91(phox), p22(phox), p40(phox), p47(phox), p67(phox) and Rac 1 proteins. In HPM incubated with NADPH and guanosine triphosphate (GTP), α(1)-AR-mediated H(2)O(2) synthesis required all of these proteins except for p40(phox). A functional link between α(1)-AR and NOX was identified as the Gα(13) protein. Alpha(1)-AR stimulation in hepatocytes promotes Rac1-GTP generation, a necessary step for H(2)O(2) synthesis. Negative cross talk between α(1)-/β-ARs for H(2)O(2) synthesis was observed in HPM. In addition, negative cross talk of α(1)-AR via H(2)O(2) to β-AR-mediated stimulation was recorded in hepatocyte gluconeogenesis and ureagenesis, probably involving aquaporine activity. Based on previous work we suggest that H(2)O(2), generated after NOX2 activation by α(1)-AR lightening in hepatocytes, reacts with cAMP-dependent protein kinase A (PKA) subunits to form an oxidized PKA, insensitive to cAMP activation that prevented any rise in the rate of gluconeogenesis and ureagenesis.

journal_name

Free Radic Res

journal_title

Free radical research

authors

Diaz-Cruz A,Vilchis-Landeros MM,Guinzberg R,Villalobos-Molina R,Piña E

doi

10.3109/10715762.2011.627920

subject

Has Abstract

pub_date

2011-11-01 00:00:00

pages

1366-78

issue

11-12

eissn

1071-5762

issn

1029-2470

journal_volume

45

pub_type

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