Carvedilol binding to β2-adrenergic receptors inhibits CFTR-dependent anion secretion in airway epithelial cells
| Autor: | Peter J. Maniak, Scott M. O'Grady, Elizabeth R. Peitzman, Nathan A. Zaidman |
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| Rok vydání: | 2016 |
| Předmět: |
Anions
0301 basic medicine Pulmonary and Respiratory Medicine medicine.medical_specialty Arrestins Physiology Adrenergic beta-Antagonists Carbazoles Cystic Fibrosis Transmembrane Conductance Regulator Pharmacology Propanolamines 03 medical and health sciences Physiology (medical) Internal medicine Cyclic AMP medicine Humans Inverse agonist Receptor Carvedilol Cells Cultured beta-Arrestins biology Chemistry Beta-Arrestins Antagonist Epithelial Cells Cell Biology Cystic fibrosis transmembrane conductance regulator 030104 developmental biology Endocrinology Call for Papers biology.protein Receptors Adrenergic beta-2 Signal transduction Signal Transduction medicine.drug |
| Zdroj: | American Journal of Physiology-Lung Cellular and Molecular Physiology. 310:L50-L58 |
| ISSN: | 1522-1504 1040-0605 |
| Popis: | 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 Iscresulted 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 Iscwas 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. |
| Databáze: | OpenAIRE |
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