Induction of cardiac fibrosis by β-blocker in G protein-independent and G protein-coupled receptor kinase 5/β-arrestin2-dependent signaling pathways

Michio Nakaya, Satsuki Chikura, Kenji Watari, Natsumi Mizuno, Koji Mochinaga, Supachoke Mangmool, Satoru Koyanagi, Shigehiro Ohdo, Yoji Sato, Tomomi Ide, Motohiro Nishida, Hitoshi Kurose

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

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 β1-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 β1- adrenergic receptor and β-arrestin2, but not β-arrestin1. The interaction between β1-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-arrestindependent signaling is a reason for the diversity of the effectiveness of β-blockers.

Original languageEnglish
Pages (from-to)35669-35677
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number42
DOIs
Publication statusPublished - Oct 12 2012

Fingerprint

G-Protein-Coupled Receptor Kinase 5
Metoprolol
GTP-Binding Proteins
Fibrosis
Arrestin
Adrenergic Receptors
Ligands
G-Protein-Coupled Receptors
Cell signaling
Adrenergic Agonists
Cardiac Myocytes
Knockout Mice
Genes
Gene Expression

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Induction of cardiac fibrosis by β-blocker in G protein-independent and G protein-coupled receptor kinase 5/β-arrestin2-dependent signaling pathways. / Nakaya, Michio; Chikura, Satsuki; Watari, Kenji; Mizuno, Natsumi; Mochinaga, Koji; Mangmool, Supachoke; Koyanagi, Satoru; Ohdo, Shigehiro; Sato, Yoji; Ide, Tomomi; Nishida, Motohiro; Kurose, Hitoshi.

In: Journal of Biological Chemistry, Vol. 287, No. 42, 12.10.2012, p. 35669-35677.

Research output: Contribution to journalArticle

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T1 - Induction of cardiac fibrosis by β-blocker in G protein-independent and G protein-coupled receptor kinase 5/β-arrestin2-dependent signaling pathways

AU - Nakaya, Michio

AU - Chikura, Satsuki

AU - Watari, Kenji

AU - Mizuno, Natsumi

AU - Mochinaga, Koji

AU - Mangmool, Supachoke

AU - Koyanagi, Satoru

AU - Ohdo, Shigehiro

AU - Sato, Yoji

AU - Ide, Tomomi

AU - Nishida, Motohiro

AU - Kurose, Hitoshi

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