How Carvedilol activates β<sub>2</sub>-adrenoceptors.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 36402762.
- Also identified by DOI 10.1038/s41467-022-34765-w and PMC identifier 9675828.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 β<sub>1</sub>-adrenoceptors, arrestin-biased signalling via β<sub>2</sub>-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 β<sub>2</sub>ARs. Because a clear understanding of how drugs act is imperative to data interpretation in basic and clinical research, to the stratification of clinical trials or to the monitoring of drug effects on the target pathway, the mechanistic insight gained here provides a foundation for the rational development of signalling prototypes that target the β-adrenoceptor system.
Medical subject headings
- Adrenergic beta-Antagonists
- Myocardial Infarction