β-adrenergic receptor signaling mediated by β-arrestins and its potential role in heart failure

Abstract

The lethality of heart failure, particularly in the context of post-acute sequelae SARS-CoV-2 infection-related myocarditis, necessitates the discovery of the cellular pathways implicated in cardiovascular disease. We summarize the signaling mechanisms of the catecholamine-binding β-adrenergic receptors (β-ARs), with an emphasis on the role of β-arrestins. β-ARs, a subset of G protein-coupled receptors (GPCRs), canonically propagate signals through heterotrimeric G proteins. However, since their discovery in the late 1980s, β-arrestins have been shown to both (i) quench G protein signaling and (ii) initiate their own independent signaling cascades, which is influenced by posttranslational modifications. β-arrestin-biased agonism by the beta-blocker carvedilol and its allosteric modulation can serve a cardioprotective role. The increasingly labyrinthine nature of GPCR signaling suggests that ligand-dependent β-AR signaling, either stimulated by an agonist or blocked by an antagonist, is selectively enhanced or suppressed by allosteric modulations, which are orchestrated by novel drugs or endogenous posttranslational modifications.