Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany.
Research Training Group 1873, University of Bonn, 53127, Bonn, Germany.
Nat Commun. 2022 Nov 19;13(1):7109. doi: 10.1038/s41467-022-34765-w.
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-adrenoceptors, arrestin-biased signalling via β-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 βARs. 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.
卡维地洛是改善心肌梗死后生存的最有效的β受体阻滞剂之一。然而，卡维地洛实现这种优越临床效果的机制仍不清楚。除了β肾上腺素受体阻断作用外，β肾上腺素受体的阻滞偏向信号传递被认为是一种解释其生存益处的分子机制。在这里，我们提供了一种替代机制来合理化卡维地洛的细胞信号传递。使用 CRISPR/Cas9 基因组编辑的原代和永生化细胞，缺乏 G 蛋白或阻滞蛋白；并结合生物、生化和信号转导测定以及分子动力学模拟，我们证明 G 蛋白通过βAR 驱动所有可检测到的卡维地洛信号传递。由于对药物作用机制的清晰理解对于基础和临床研究中的数据分析、临床试验的分层或药物对靶途径的影响的监测至关重要，因此这里获得的机制见解为靶向β肾上腺素受体系统的信号传递原型的合理开发提供了基础。
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