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β‐adrenergic receptor agonists known to stimulate β‐arrestin‐dependent signaling inhibit CFTR activity, cell migration and airway epithelial restitution
Author(s) -
Peitzman Elizabeth R.,
O'Grady Scott M.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1145.4
Subject(s) - carvedilol , chemistry , stimulation , agonist , endocrinology , medicine , receptor , receptor antagonist , epinephrine , pharmacology , antagonist , biology , heart failure
Previously, the β‐adrenergic receptor antagonist carvedilol was shown to function as an inverse agonist, capable of stabilizing a receptor conformation uncoupled from G s , but able to stimulate β‐arrestin‐dependent signaling and induce desensitization. In this study, measurements of cell migration using impedance sensing technology showed that stimulation of normal human bronchial epithelial cells and Calu‐3 cells with epinephrine or salbutamol reduced cell migration and increased the time required for epithelial restitution. Pretreatment with CFTR inhibitor CFTR inh ‐172 or CFTR silencing blocked the effect of epinephrine and salbutamol. Carvedilol also inhibited migration and restitution to the same extent as epinephrine and salbutamol. Moreover, short circuit current (Isc) measurements revealed that unlike β‐agonists which increased Isc, carvedilol decreased basal current and the peak current following 8‐cpt cAMP stimulation. Pretreatment with carvedilol also abolished the effect of 8‐cpt cAMP on Cl − secretion. The carvedilol effect was abolished by pretreatment with the β 2 ‐adrenergic receptor antagonist ICI‐118551, which also rescued Clsecretion following 8‐cpt cAMP stimulation. Therefore, agonists that activate β‐arrestin signaling and facilitate β 2 adrenergic receptor desensitization inhibit cell migration and wound repair by a mechanism involving CFTR inhibition.