Induction of Cardiac Fibrosis by β-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/β-Arrestin2-dependent Signaling Pathways
| Autor: | Koji Mochinaga, Tomomi Ide, Shigehiro Ohdo, Yoji Sato, Motohiro Nishida, Hitoshi Kurose, Natsumi Mizuno, Michio Nakaya, Satoru Koyanagi, Satsuki Chikura, Kenji Watari, Supachoke Mangmool |
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| Rok vydání: | 2012 |
| Předmět: |
G-Protein-Coupled Receptor Kinase 5
Cell signaling genetic structures Heart Diseases Arrestins Cardiac fibrosis G protein Muscle Proteins Pharmacology Biology Biochemistry Rats Sprague-Dawley Mice medicine Animals Humans cardiovascular diseases Molecular Biology beta-Arrestins G protein-coupled receptor Mice Knockout G protein-coupled receptor kinase Beta-Arrestins Cell Biology medicine.disease Adrenergic beta-1 Receptor Antagonists Fibrosis Rats HEK293 Cells sense organs Signal transduction circulatory and respiratory physiology Metoprolol Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 287:35669-35677 |
| ISSN: | 0021-9258 |
| Popis: | G-protein coupled receptors (GPCRs) have long been known as receptors that activate G protein-dependent cellular signaling pathways. In addition to the G protein-dependent pathways, recent reports have revealed that several ligands called "biased ligands" elicit G protein-independent and β-arrestin-dependent signaling through GPCRs (biased agonism). Several β-blockers are known as biased ligands. All β-blockers inhibit the binding of agonists to the β-adrenergic receptors. In addition to β-blocking action, some β-blockers are reported to induce cellular responses through G protein-independent and β-arrestin-dependent signaling pathways. However, the physiological significance induced by the β-arrestin-dependent pathway remains much to be clarified in vivo. Here, we demonstrate that metoprolol, a β(1)-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and β-arrestin2-dependent pathway. Metoprolol, a β-blocker, increased the expression of fibrotic genes responsible for cardiac fibrosis in cardiomyocytes. Furthermore, metoprolol induced the interaction between β(1)-adrenergic receptor and β-arrestin2, but not β-arrestin1. The interaction between β(1)-adrenergic receptor and β-arrestin2 by metoprolol was impaired in the G protein-coupled receptor kinase 5 (GRK5)-knockdown cells. Metoprolol-induced cardiac fibrosis led to cardiac dysfunction. However, the metoprolol-induced fibrosis and cardiac dysfunction were not evoked in β-arrestin2- or GRK5-knock-out mice. Thus, metoprolol is a biased ligand that selectively activates a G protein-independent and GRK5/β-arrestin2-dependent pathway, and induces cardiac fibrosis. This study demonstrates the physiological importance of biased agonism, and suggests that G protein-independent and β-arrestin-dependent signaling is a reason for the diversity of the effectiveness of β-blockers. |
| Databáze: | OpenAIRE |
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