ArticleBritish journal of pharmacology2015
Hydrogen peroxide stimulation of CFTR reveals an Epac-mediated, soluble AC-dependent cAMP amplification pathway common to GPCR signalling.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 34 citations in OpenAlex.
- Biochemical pharmacology of adenylyl cyclases in cancer.Biochemical pharmacology · 2024Review
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- Soluble cyclase-mediated nuclear cAMP synthesis is sufficient for cell proliferation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- International Union of Basic and Clinical Pharmacology. CIX. Differences and Similarities between Human and Rodent Prostaglandin EPharmacological reviews · 2020Article
- Kv7 Channels in Lung Diseases.Frontiers in physiology · 2020Review
- Neural control of body-plan axis in regenerating planaria.PLoS computational biology · 2019Article
- Lipid Peroxidation Drives Renal Cyst GrowthJournal of the American Society of Nephrology : JASN · 2019Article
- Oxidative stress, autophagy and airway ion transport.American journal of physiology. Cell physiology · 2019Review
- Mammalian pigmentation is regulated by a distinct cAMP-dependent mechanism that controls melanosome pH.Science signaling · 2018Article
- Pharmacological modulation of the COPharmacology & therapeutics · 2018Review
- CFTR supports cell death through ROS-dependent activation of TMEM16F (anoctamin 6).Pflugers Archiv : European journal of physiology · 2018Article
- Cigarette smoke activates CFTR through ROS-stimulated cAMP signaling in human bronchial epithelial cells.American journal of physiology. Cell physiology · 2018Article
- Endocrinology and the brain: corticotropin-releasing hormone signaling.Endocrine connections · 2017Review
- Impaired PGE2-stimulated Cl- and HCO3- secretion contributes to cystic fibrosis airway disease.PloS one · 2017Article
- Spatial resolution of cAMP signaling by soluble adenylyl cyclase.The Journal of cell biology · 2016Article
- Different cAMP sources are critically involved in G protein-coupled receptor CRHR1 signaling.The Journal of cell biology · 2016Article
- The β2-adrenoceptor activates a positive cAMP-calcium feedforward loop to drive breast cancer cell invasion.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2016Article
- Soluble adenylyl cyclase mediates hydrogen peroxide-induced changes in epithelial barrier function.Respiratory research · 2016Article
- Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists.Journal of medicinal chemistry · 2015Article
- Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window".Scientific reports · 2015Article
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3 authors at 1 institution in 1 country.
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Abstract
background and purposeH2 O2 is widely understood to regulate intracellular signalling. In airway epithelia, H2 O2 stimulates anion secretion primarily by activating an autocrine PGE2 signalling pathway via EP4 and EP1 receptors to initiate cytic fibrosis transmembrane regulator (CFTR)-mediated Cl(-) secretion. This study investigated signalling downstream of the receptors activated by H2 O2 . EXPERIMENTAL APPROACH: Anion secretion by differentiated bronchial epithelial cells was measured in Ussing chambers during stimulation with H2 O2 , an EP4 receptor agonist or β2 -adrenoceptor agonist in the presence and absence of inhibitors of ACs and downstream effectors. Intracellular calcium ([Ca(2+) ]I ) changes were followed by microscopy using fura-2-loaded cells and PKA activation followed by FRET microscopy. KEY
resultsTransmembrane adenylyl cyclase (tmAC) and soluble AC (sAC) were both necessary for H2 O2 and EP4 receptor-mediated CFTR activation in bronchial epithelia. H2 O2 and EP4 receptor agonist stimulated tmAC to increase exchange protein activated by cAMP (Epac) activity that drives PLC activation to raise [Ca(2+) ]i via Ca(2+) store release (and not entry). Increased [Ca(2+) ]i led to sAC activation and further increases in CFTR activity. Stimulation of sAC did not depend on changes in [HCO3 (-) ]. Ca(2+) -activated apical KCa 1.1 channels and cAMP-activated basolateral KV 7.1 channels contributed to H2 O2 -stimulated anion currents. A similar Epac-mediated pathway was seen following β2 -adrenoceptor or forskolin stimulation. CONCLUSIONS AND IMPLICATIONS: H2 O2 initiated a complex signalling cascade that used direct stimulation of tmACs by Gαs followed by Epac-mediated Ca(2+) crosstalk to activate sAC. The Epac-mediated Ca(2+) signal constituted a positive feedback loop that amplified CFTR anion secretion following stimulation of tmAC by a variety of stimuli.
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