β-Arrestin–mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection

TLDR

Deleterious effects on the heart from chronic β‑adrenergic receptor stimulation are classically driven by Gs‑dependent adenylyl cyclase activation. The study identifies a novel β‑arrestin–mediated β1‑adrenergic receptor signaling pathway to EGFR using in vitro and in vivo systems. The pathway involves β‑arrestin–dependent EGFR transactivation that requires GRK5/6 and is independent of G protein signaling. In chronically stimulated mice, the pathway activates cardioprotective mechanisms that counter catecholamine toxicity, indicating that drugs blocking G protein signaling yet stimulating β‑arrestin–mediated cytoprotection could be a new therapeutic class.

Abstract

Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby β-arrestins mediate β1AR signaling to the EGFR. This β-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 cardioprotective 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 β-arrestin–mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.