How Carvedilol activates β₂-adrenoceptors.

ABSTRACT: Carvedilol is among the most effective β-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of β₁-adrenoceptors, arrestin-biased signalling via β₂-adrenoceptors is a molecular mechanism proposed to explain the survival benefits. Here, we offer an alternative mechanism to rationalize carvedilol's cellular signalling. Using primary and immortalized cells genome-edited by CRISPR/Cas9 to lack either G proteins or arrestins; and combining biological, biochemical, and signalling assays with molecular dynamics simulations, we demonstrate that G proteins drive all detectable carvedilol signalling through β₂ARs. Because a clear understanding of

SUBMITTER: Benkel T 

PROVIDER: S-EPMC9675828 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature