Carvedilol binding to β2-adrenergic receptors inhibits CFTR-dependent anion secretion in airway epithelial cells

Elizabeth R Peitzman, Nathan A. Zaidman, Peter J Maniak, Scott M O'Grady

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3 Citations (Scopus)

Abstract

Carvedilol functions as a nonselective-adrenergic receptor (AR)/ 1-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-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current (Isc) measurements using human airway epithelial cells revealed that, unlike-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3’,5’-cyclic monophosphatestimulated current. The decrease in Isc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with theβ2-AR antagonist ICI-118551, but not the 1-AR antagonist atenolol or the 1-AR antagonist prazosin, indicating that its inhibitory effect on Isc was mediated through interactions with apical 2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubuledisrupting compound nocodazole. Furthermore, immunocytochemis-try 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 2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.

Original languageEnglish (US)
Pages (from-to)L50-L58
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume310
Issue number1
DOIs
StatePublished - Jan 1 2016

Fingerprint

Cystic Fibrosis Transmembrane Conductance Regulator
Adrenergic Receptors
Anions
Epithelial Cells
Adrenergic Antagonists
Arrestin
Nocodazole
Adrenergic Agonists
Atenolol
Membranes
Prazosin
carvedilol
Treatment Failure
GTP-Binding Proteins
Adenosine
Epinephrine
Heart Failure
Western Blotting
Hypertension

Keywords

  • Bias ligands
  • Carvedilol
  • Inverse agonists
  • β-arrestin signaling

Cite this

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title = "Carvedilol binding to β2-adrenergic receptors inhibits CFTR-dependent anion secretion in airway epithelial cells",
abstract = "Carvedilol functions as a nonselective-adrenergic receptor (AR)/ 1-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-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current (Isc) measurements using human airway epithelial cells revealed that, unlike-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3’,5’-cyclic monophosphatestimulated current. The decrease in Isc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with theβ2-AR antagonist ICI-118551, but not the 1-AR antagonist atenolol or the 1-AR antagonist prazosin, indicating that its inhibitory effect on Isc was mediated through interactions with apical 2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubuledisrupting compound nocodazole. Furthermore, immunocytochemis-try 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 2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.",
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T1 - Carvedilol binding to β2-adrenergic receptors inhibits CFTR-dependent anion secretion in airway epithelial cells

AU - Peitzman, Elizabeth R

AU - Zaidman, Nathan A.

AU - Maniak, Peter J

AU - O'Grady, Scott M

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N2 - Carvedilol functions as a nonselective-adrenergic receptor (AR)/ 1-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-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current (Isc) measurements using human airway epithelial cells revealed that, unlike-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3’,5’-cyclic monophosphatestimulated current. The decrease in Isc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with theβ2-AR antagonist ICI-118551, but not the 1-AR antagonist atenolol or the 1-AR antagonist prazosin, indicating that its inhibitory effect on Isc was mediated through interactions with apical 2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubuledisrupting compound nocodazole. Furthermore, immunocytochemis-try 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 2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.

AB - Carvedilol functions as a nonselective-adrenergic receptor (AR)/ 1-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-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current (Isc) measurements using human airway epithelial cells revealed that, unlike-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3’,5’-cyclic monophosphatestimulated current. The decrease in Isc resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with theβ2-AR antagonist ICI-118551, but not the 1-AR antagonist atenolol or the 1-AR antagonist prazosin, indicating that its inhibitory effect on Isc was mediated through interactions with apical 2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubuledisrupting compound nocodazole. Furthermore, immunocytochemis-try 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 2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.

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