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 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.
Highlights
It is not known whether a -blocker, metoprolol, induces physiological responses through -arrestins in vivo
We discovered that -arrestin2 and G protein-coupled receptor kinase 5 (GRK5) are involved in this G protein-independent fibrotic pathway in vitro and in vivo
Administration of Metoprolol to Wild Type Normal Mice Induces Cardiac Fibrosis—During the analysis of the effects of -blockers on heart failure, we found that long-term treatment with metoprolol, but not with propranolol and carvedilol, to wild type normal ddY mice induced perivascular fibrosis in their hearts (Fig. 1, A and B)
Summary
It is not known whether a -blocker, metoprolol, induces physiological responses through -arrestins in vivo. We demonstrate that metoprolol, a 1-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and -arrestin2-dependent pathway. In addition to the blocking effects, some -blockers have been shown to evoke signal transduction through the -adrenergic receptors in G protein-independent and -arrestin-dependent manner (19 –21). We found that long-term administration of metoprolol, an inverse agonist for the 1-adrenergic receptor, to mice induced cardiac fibrosis, which is thought to be deleterious for the heart by stiffening it and inhibiting the electrical conductivity between cardiomyocytes. We revealed that this fibrotic pathway was mediated through the 1-adrenergic receptor in a G protein-independent manner. We discovered that -arrestin and GRK5 are involved in this G protein-independent fibrotic pathway in vitro and in vivo
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