期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34765-w
关键词
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资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [290847012/FOR2372, KO4095/4-1, KO4095/5-1, RTG1873, 214362475/GRK1873/2]
- Luxembourg National Research Fund (INTER/FWO Nanokine) [15/10358798, 20/15084569]
- PoC Megakine [19/14209621, 7.8504.20]
- Wellcome Trust Senior Research Fellowship [212313/Z/18/Z, CA18133]
- COST (European Cooperation in Science and Technology)
This study provides an alternative mechanism for carvedilol's cellular signaling, demonstrating that G proteins drive all detectable signals through beta(2)-adrenoceptors.
Carvedilol is among the most effective beta-blockers for improving survival after myocardial infarction. Yet the mechanisms by which carvedilol achieves this superior clinical profile are still unclear. Beyond blockade of beta(1)-adrenoceptors, arrestin-biased signalling via beta(2)-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 beta(2)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 beta-adrenoceptor system. How carvedilol, a beta 1-blocker, activates beta 2-adrenoceptors, is unclear. Here, the authors resolve this enigma and show that carvedilol drives all of its detectable cellular beta 2-adrenoceptor signals by slow and low efficacy G protein activation.
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