Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2016 Mar 18;29112:6423-32. doi: 10.1074/jbc.M115.664854.
Show Gene links
Show Anatomy links
Dual Oxidase 2 (Duox2) Regulates Pannexin 1-mediated ATP Release in Primary Human Airway Epithelial Cells via Changes in Intracellular pH and Not H2O2 Production.
Krick S, Wang J, St-Pierre M, Gonzalez C, Dahl G, Salathe M.
???displayArticle.abstract???
Human airway epithelial cells express pannexin 1 (Panx1) channels to release ATP, which regulates mucociliary clearance. Airway inflammation causes mucociliary dysfunction. Exposure of primary human airway epithelial cell cultures to IFN-γ for 48 h did not alter Panx1 protein expression but significantly decreased ATP release in response to hypotonic stress. The IFN-γ-induced functional down-regulation of Panx1 was due to the up-regulation of dual oxidase 2 (Duox2). Duox2 suppression by siRNA led to an increase in ATP release in control cells and restoration of ATP release in cells treated with IFN-γ. Both effects were reduced by the pannexin inhibitor probenecid. Duox2 up-regulation stoichiometrically increases H2O2 and proton production. H2O2 inhibited Panx1 function temporarily by formation of disulfide bonds at the thiol group of its terminal cysteine. Long-term exposure to H2O2, however, had no inhibitory effect. To assess the role of cellular acidification upon IFN-γ treatment, fully differentiated airway epithelial cells were exposed to ammonium chloride to alkalinize the cytosol. This led to a 2-fold increase in ATP release in cells treated with IFN-γ that was also inhibited by probenecid. Duox2 knockdown also partially corrected IFN-γ-mediated acidification. The direct correlation between intracellular pH and Panx1 open probability was shown in oocytes. Therefore, airway epithelial cells release less ATP in response to hypotonic stress in an inflammatory environment (IFN-γ exposure). Decreased Panx1 function is a response to cell acidification mediated by IFN-γ-induced up-regulation of Duox2, representing a novel mechanism for mucociliary dysfunction in inflammatory airway diseases.
Anderson,
The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis.
2015, Pubmed
Anderson,
The Relationship of Mucus Concentration (Hydration) to Mucus Osmotic Pressure and Transport in Chronic Bronchitis.
2015,
Pubmed Bao,
Pannexin membrane channels are mechanosensitive conduits for ATP.
2004,
Pubmed
,
Xenbase Beckel,
Mechanosensitive release of adenosine 5'-triphosphate through pannexin channels and mechanosensitive upregulation of pannexin channels in optic nerve head astrocytes: a mechanism for purinergic involvement in chronic strain.
2014,
Pubmed Bienert,
Aquaporin-facilitated transmembrane diffusion of hydrogen peroxide.
2014,
Pubmed Braiman,
Intracellular stores maintain stable cytosolic Ca(2+) gradients in epithelial cells by active Ca(2+) redistribution.
2001,
Pubmed Bruzzone,
Pannexins, a family of gap junction proteins expressed in brain.
2003,
Pubmed
,
Xenbase Button,
Mechanosensitive ATP release maintains proper mucus hydration of airways.
2013,
Pubmed Conner,
H2O2 stimulates cystic fibrosis transmembrane conductance regulator through an autocrine prostaglandin pathway, using multidrug-resistant protein-4.
2013,
Pubmed Davis,
Goblet cell degranulation in isolated canine tracheal epithelium: response to exogenous ATP, ADP, and adenosine.
1992,
Pubmed Duffy,
Regulation of connexin43 protein complexes by intracellular acidification.
2004,
Pubmed Fragoso,
Transcellular thiocyanate transport by human airway epithelia.
2004,
Pubmed Fulcher,
Well-differentiated human airway epithelial cell cultures.
2005,
Pubmed Gattas,
Oxidative epithelial host defense is regulated by infectious and inflammatory stimuli.
2009,
Pubmed Geary,
Role of CNP in human airways: cGMP-mediated stimulation of ciliary beat frequency.
1995,
Pubmed González-Nieto,
Regulation of neuronal connexin-36 channels by pH.
2008,
Pubmed
,
Xenbase Harper,
Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium.
2005,
Pubmed Isakson,
Pannexin-1 as a potentiator of ligand-gated receptor signaling.
2014,
Pubmed Kim,
Gating connexin 43 channels reconstituted in lipid vesicles by mitogen-activated protein kinase phosphorylation.
1999,
Pubmed Kumar,
Interferon-γ, pulmonary macrophages and airway responsiveness in asthma.
2012,
Pubmed Kumar,
Interferon-gamma as a possible target in chronic asthma.
2006,
Pubmed Lethem,
Nucleotide regulation of goblet cells in human airway epithelial explants: normal exocytosis in cystic fibrosis.
1993,
Pubmed Li,
Oxidation regulates cloned neuronal voltage-dependent Ca2+ channels expressed in Xenopus oocytes.
1998,
Pubmed
,
Xenbase Locovei,
Activation of pannexin 1 channels by ATP through P2Y receptors and by cytoplasmic calcium.
2006,
Pubmed
,
Xenbase Locovei,
Pannexin 1 in erythrocytes: function without a gap.
2006,
Pubmed
,
Xenbase Ma,
Pharmacological characterization of pannexin-1 currents expressed in mammalian cells.
2009,
Pubmed Manzanares,
Airway Surface Dehydration by Transforming Growth Factor β (TGF-β) in Cystic Fibrosis Is Due to Decreased Function of a Voltage-dependent Potassium Channel and Can Be Rescued by the Drug Pirfenidone.
2015,
Pubmed Manzanares,
Functional apical large conductance, Ca2+-activated, and voltage-dependent K+ channels are required for maintenance of airway surface liquid volume.
2011,
Pubmed Manzanares,
IFN-γ-mediated reduction of large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel activity in airway epithelial cells leads to mucociliary dysfunction.
2014,
Pubmed Mason,
Regulation of transepithelial ion transport and intracellular calcium by extracellular ATP in human normal and cystic fibrosis airway epithelium.
1991,
Pubmed Miller,
Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling.
2010,
Pubmed Morley,
Intramolecular interactions mediate pH regulation of connexin43 channels.
1996,
Pubmed
,
Xenbase Murali,
Angiotensin II mobilizes intracellular calcium and activates pannexin-1 channels in rat carotid body type II cells via AT1 receptors.
2014,
Pubmed Nagai,
Dual oxidase 1 and 2 expression in airway epithelium of smokers and patients with mild/moderate chronic obstructive pulmonary disease.
2008,
Pubmed Negoro,
Pannexin 1 channels play essential roles in urothelial mechanotransduction and intercellular signaling.
2014,
Pubmed Nlend,
Calcium-mediated, purinergic stimulation and polarized localization of calcium-sensitive adenylyl cyclase isoforms in human airway epithelia.
2007,
Pubmed Okada,
Physiological regulation of ATP release at the apical surface of human airway epithelia.
2006,
Pubmed Panzner,
Marked up-regulation of T lymphocytes and expression of interleukin-9 in bronchial biopsies from patients With chronic bronchitis with obstruction.
2003,
Pubmed Penuela,
Pannexin 1 and pannexin 3 are glycoproteins that exhibit many distinct characteristics from the connexin family of gap junction proteins.
2007,
Pubmed Pfahnl,
Localization of a voltage gate in connexin46 gap junction hemichannels.
1998,
Pubmed
,
Xenbase Qiu,
A permeant regulating its permeation pore: inhibition of pannexin 1 channels by ATP.
2009,
Pubmed
,
Xenbase Ransford,
Pannexin 1 contributes to ATP release in airway epithelia.
2009,
Pubmed
,
Xenbase Schlief,
H2O2-induced chloride currents are indicative of an endogenous Na(+)-Ca2+ exchange mechanism in Xenopus oocytes.
1995,
Pubmed
,
Xenbase Schmid,
Nucleotide-mediated airway clearance.
2011,
Pubmed Schwarzer,
NADPH oxidase-dependent acid production in airway epithelial cells.
2004,
Pubmed Seminario-Vidal,
Rho signaling regulates pannexin 1-mediated ATP release from airway epithelia.
2011,
Pubmed Silverman,
The pannexin 1 channel activates the inflammasome in neurons and astrocytes.
2009,
Pubmed
,
Xenbase Sosinsky,
Pannexin channels are not gap junction hemichannels.
2011,
Pubmed Sutto,
Regulation of human airway ciliary beat frequency by intracellular pH.
2004,
Pubmed Tarran,
Basal chloride currents in murine airway epithelial cells: modulation by CFTR.
1998,
Pubmed Thimm,
Calcium-dependent open/closed conformations and interfacial energy maps of reconstituted hemichannels.
2005,
Pubmed Trexler,
Rapid and direct effects of pH on connexins revealed by the connexin46 hemichannel preparation.
1999,
Pubmed
,
Xenbase Wang,
SCAM analysis of Panx1 suggests a peculiar pore structure.
2010,
Pubmed
,
Xenbase
