title: Protective effects of glycyrrhizin against β₂-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).
authors.affiliation: College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Hou
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.forename: Gang
authors.initials: G
authors.lastname: Bai
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000420:Albuterol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019390:Arrestins / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002966:Clathrin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D004705:Endocytosis / Q000187:drug effects*; D019695:Glycyrrhizic Acid / Q000494:pharmacology*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D000318:Adrenergic beta-Agonists; D019390:Arrestins; D002966:Clathrin; D017931:DNA Primers; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D000071557:beta-Arrestins; D019695:Glycyrrhizic Acid; D000242:Cyclic AMP; D000420:Albuterol