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

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 ?-arrestin-dependent signaling through GPCRs (biased agonism). Several ?-blockers are known as biased ligands. All ?-blockers inhibit the binding of agonists to the ?-adrenergic receptors. In addition to ?-blocking action, some ?-blockers are reported to induce cellular responses through G protein-independent and ?-arrestin-dependent signaling pathways. However, the physiological significance induced by the ?-arrestin-dependent pathway remains much to be clarified in vivo. Here, we demonstrate that metoprolol, a ?(1)-adrenergic receptor-selective blocker, could induce cardiac fibrosis through a G protein-independent and ?-arrestin2-dependent pathway. Metoprolol, a ?-blocker, increased the expression of fibrotic genes responsible for cardiac fibrosis in cardiomyocytes. Furthermore, metoprolol induced the interaction between ?(1)-adrenergic receptor and ?-arrestin2, but not ?-arrestin1. The interaction between ?(1)-adrenergic receptor and ?-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 ?-arrestin2- or GRK5-knock-out mice. Thus, metoprolol is a biased ligand that selectively activates a G protein-independent and GRK5/?-arrestin2-dependent pathway, and induces cardiac fibrosis. This study demonstrates the physiological importance of biased agonism, and suggests that G protein-independent and ?-arrestin-dependent signaling is a reason for the diversity of the effectiveness of ?-blockers.

SUBMITTER: Nakaya M

PROVIDER: S-EPMC3471751 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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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 M Chikura Satsuki S Watari Kenji K Mizuno Natsumi N Mochinaga Koji K Mangmool Supachoke S Koyanagi Satoru S Ohdo Shigehiro S Sato Yoji Y Ide Tomomi T Nishida Motohiro M Kurose Hitoshi H

The Journal of biological chemistry 20120810 42

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-block ...[more]

PMID: 22888001

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Project description:prolonged P2Y-receptor signalling can cause vasoconstriction leading to hypertension, vascular smooth muscle hypertrophy, and hyperplasia. G protein-coupled receptor signalling is negatively regulated by G protein-coupled receptor kinases (GRKs) and arrestin proteins, preventing prolonged or inappropriate signalling. This study investigates whether GRKs and arrestins regulate uridine 5'-triphosphate (UTP)-stimulated contractile signalling in adult Wistar rat mesenteric arterial smooth muscle cells (MSMCs).mesenteric arteries contracted in response to UTP challenge: When an EC(50) UTP concentration (30 µM, 5 min) was added 5 min before (R(1)) and after (R(2)) the addition of a maximal UTP concentration (R(max): 100 µM, 5 min), R(2) responses were decreased relative to R(1), indicating desensitization. UTP-induced P2Y-receptor desensitization of phospholipase C signalling was studied in isolated MSMCs transfected with an inositol 1,4,5-trisphosphate biosensor and/or loaded with Ca(2+)-sensitive dyes. A similar protocol (R(1)/R(2) = 10 µM; R(max) = 100 µM, applied for 30 s) revealed markedly reduced R(2) when compared with R(1) responses. MSMCs were transfected with dominant-negative GRKs or siRNAs targeting specific GRK/arrestins to probe their respective roles in P2Y-receptor desensitization. GRK2 inhibition, but not GRK3, GRK5, or GRK6, attenuated P2Y-receptor desensitization. siRNA-mediated knockdown of arrestin2 attenuated UTP-stimulated P2Y-receptor desensitization, whereas arrestin3 depletion did not. Specific siRNA knockdown of the P2Y(2)-receptor almost completely abolished UTP-stimulated IP(3)/Ca(2+) signalling, strongly suggesting that our study is specifically characterizing this purinoceptor subtype.these new data highlight roles of GRK2 and arrestin2 as important regulators of UTP-stimulated P2Y(2)-receptor responsiveness in resistance arteries, emphasizing their potential importance in regulating vasoconstrictor signalling pathways implicated in vascular disease.

Dataset Information

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

Publications

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

Similar Datasets

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