Imipramine Inhibits Cl− Secretion by Desensitization of β-Adrenergic Receptors in Calu-3 Human Airway Cells

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

“…Previously, experiments with 16HBE14o Ϫ cells (immortalized human bronchial epithelial cells) and Calu-3 cells (an adenocarcinoma cell line derived from human airways) demonstrated that both cell lines express ␤ 2 -AR mRNA and that stimulation with isoproterenol increased cAMP accumulation that was inhibited by pretreatment with the ␤ 2 -AR-selective antagonist ICI-118551, but not CPG 20712A, a ␤ 1 -AR-selective antagonist (1,5). Furthermore, stimulation of Calu-3 cells with isoproterenol or epinephrine increased cystic fibrosis transmembrane conductance regulator (CFTR)-dependent anion secretion by raising intracellular cAMP concentration and mobilizing intracellular calcium from internal stores (4,19,31). Additionally, the short-acting ␤ 2 -AR-selective agonist salbutamol and the long-acting agonist salmeterol have been shown to modulate paracellular permeability of normal human bronchial epithelial cells (39).…”

“…Furthermore, carvedilol has been shown to function as an inverse agonist by blocking G protein activation while stimulating ␤-arrestinassociated signaling pathways (14). Structural studies involving the use of site-specific 19 F-nuclear magnetic resonance labels within the ␤ 2 -AR showed that the cytoplasmic ends of helicies 6 and 7 assume distinct conformational states, depending on the activating ligand, with carvedilol primarily affecting the conformational states of helix 7 (18). Moreover, crystal structures of the ␤ 1 -AR bound to carvedilol showed additional interactions with helices 2, 3, and 7 and extracellular loop 2 compared with other ␤-AR blockers, and these changes may underlie the G protein-independent signaling characteristics of carvedilol and, potentially, other inverse agonists (41).…”