Protective Effects of Glycyrrhizin against .BETA.2-Adrenergic Receptor Agonist-Induced Receptor Internalization and Cell Apoptosis

Abstract

It has been reported that treatment with β₂ adrenergic receptor (β₂AR) agonist bronchodilators may result in airway β₂ARs internalization and cardiac muscle cells apoptosis. This could lead to the loss of pharmacological effect of β₂AR agonists and increase adverse cardiovascular events in asthma patients receiving β₂AR agonist therapy. Glycyrrhizin, the major bioactive component of licorice root extract, has been reported to exhibit protective effect on respiratory system. Here, we investigate the effects of glycyrrhizin against β₂AR agonist salbutamol-induced receptor internalization and cell apoptosis. In our study, the live cell confocal imaging and fixed-cell enzyme-linked immunosorbent assay (ELISA) assay revealed that glycyrrhizin significantly inhibited salbutamol-induced surface β₂AR internalization. The underlying mechanisms were then identified to be that glycyrrhizin could reduce the association of β₂ARs with β-arrestins and clathrin heavy chain as well as the level of G protein-coupled receptor kinase (GRK) mediated phosphorylation of β₂ARs. The inhibition of receptor internalization by glycyrrhizin further lead to stabilization of the β₂AR mRNA and protein expression, thus amplified the transmembrane signaling via the β₂ARs. We also proved that glycyrrhizin could profoundly attenuate salbutamol-induced early cellular apoptosis by regulating the expressions of B-cell lymphoma 2 (Bcl-2) family genes. Taken together, our results suggest that glycyrrhizin exhibits protective effects against β₂AR agonist-induced receptor internalization and cell apoptosis. These findings might have practical implications for future strategies of combined application of glycyrrhizin with β₂AR receptor agonists to improve the efficacy of bronchodilators in patients with asthma and chronic obstructive pulmonary disease (COPD).