title: Carvedilol binding to β2-adrenergic receptors inhibits CFTR-dependent anion secretion in airway epithelial cells.
abstract: Carvedilol functions as a nonselective β-adrenergic receptor (AR)/α1-AR antagonist that is used for treatment of hypertension and heart failure. Carvedilol has been shown to function as an inverse agonist, inhibiting G protein activation while stimulating β-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current (Isc) measurements using human airway epithelial cells revealed that, unlike β-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate-stimulated current. The decrease in Isc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with the β2-AR antagonist ICI-118551, but not the β1-AR antagonist atenolol or the α1-AR antagonist prazosin, indicating that its inhibitory effect on Isc was mediated through interactions with apical β2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubule-disrupting compound nocodazole. Furthermore, immunocytochemistry experiments and measurements of apical CFTR expression by Western blot analysis of biotinylated membranes revealed a decrease in the level of CFTR protein in monolayers treated with carvedilol but no significant change in monolayers treated with epinephrine. These results demonstrate that carvedilol binding to apical β2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.
authors.affiliation: Department of Animal Science, University of Minnesota, St. Paul, Minnesota; and.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Peitzman
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, St. Paul, Minnesota.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Zaidman
authors.affiliation: Department of Animal Science, University of Minnesota, St. Paul, Minnesota; and.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Maniak
authors.affiliation: Department of Animal Science, University of Minnesota, St. Paul, Minnesota; and Department of Integrative Biology and Physiology, University of Minnesota, St. Paul, Minnesota ograd001@umn.edu.
authors.forename: Scott M
authors.initials: SM
authors.lastname: O'Grady
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000838:Anions / Q000378:metabolism; D019390:Arrestins / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D011412:Propanolamines / Q000494:pharmacology*; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects*; D015398:Signal Transduction; D000071557:beta-Arrestins
chemical_list: D000319:Adrenergic beta-Antagonists; D000838:Anions; D019390:Arrestins; D002227:Carbazoles; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D000077261:Carvedilol; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C026777:ICI 118551; D000242:Cyclic AMP
keywords: bias ligands; carvedilol; inverse agonists; β-arrestin signaling