title: NADPH oxidase NOX2 defines a new antagonistic role for reactive oxygen species and cAMP/PKA in the regulation of insulin secretion.
abstract: In insulin-secreting cells, expression of NADPH oxidase (NOX), a potent source of ROS, has been reported, along with controversial findings regarding its function. Here, the role of NOXs was investigated: first by expression and cellular localization in mouse and human pancreatic islets, and then by functional studies in islets isolated from Nox isoform-specific knockout mice. Both human and mouse β-cells express NOX, in particular NOX2. With use of Nox isoform-specific knockout mice, functional analysis revealed Nox2 as the predominant isoform. In human islets, NOX2 colocalized with both insulin granules and endosome/lysosome membranes. Nox2-deficient islets stimulated with 22.8 mmol/L glucose exhibited potentiation of insulin release compared with controls, an effect confirmed with in vitro knockdown of Nox2. The enhanced secretory function in Nox2-deficient islets was associated with both lower superoxide levels and elevated cAMP concentrations. In control islets, GLP-1 and other cAMP inducers suppressed glucose-induced ROS production similarly to Nox2 deficiency. Inhibiting cAMP-dependent protein kinase reduced the secretory response in Nox2-null islets, although not in control islets. This study ascribes a new role for NOX2 in pancreatic β-cells as negative modulator of the secretory response, reducing cAMP/PKA signaling secondary to ROS generation. Results also show reciprocal inhibition between the cAMP/PKA pathway and ROS.
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.forename: Thierry
authors.initials: T
authors.lastname: Brun
authors.forename: Christine
authors.initials: C
authors.lastname: Deffert-Delbouille
authors.forename: Zahia
authors.initials: Z
authors.lastname: Mahiout
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Ma
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Krause
authors.forename: Pierre
authors.initials: P
authors.lastname: Maechler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020868:Gene Silencing; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015290:Second Messenger Systems / Q000187:drug effects; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: D007328:Insulin; D007527:Isoenzymes; D008562:Membrane Glycoproteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D017868:Cyclic AMP-Dependent Protein Kinases