期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 117, 期 9, 页码 2445-2458出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI31901
关键词
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资金
- NHLBI NIH HHS [P01 HL075443, HL56687, R01 HL056687, HL075443, HL23457] Funding Source: Medline
Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors (beta ARs), members of the 7 transmembrane receptor family, have classically been shown to result from G(s)-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby beta-arrestins mediate beta(1)AR signaling to the EGFP. This beta-arrestin-dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein-coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardio-protective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via beta-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.
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