• CE Slide 1
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  • CardioExcyte 96

    Combined impedance and MEA-like recordings
  • CardioExcyte 96

    For cardiac safety screening
  • CardioExcyte 96

    Next generation label-free cell analysis
  • CardioExcyte 96

    Intuitive data analysis & arrhythmia detection

2022 - How Carvedilol activates β2-adrenoceptors

icon sp96 CardioExcyte 96 publication in Nature Communications (2022)

Authors:

Benkel T., Zimmermann M., Zeiner J., Bravo S., Merten N., Jun Yu Lim V., Fabienne Matthees E., Drube J., Miess-Tanneberg E., Malan D., Szpakowska M., Monteleone S., Grimes J., Koszegi Z., Lanoiselée Y., O’Brien S., Pavlaki N., Dobberstein N., Inoue A., Nikolaev V., Calebiro D., Chevigné A., Sasse P., Schulz S., Hoffmann C., Kolb P., Waldhoer M., Simon K., Gomeza J., Kostenis E.

Journal:

Nature Communications (2022) doi:10.1038/s41467-022-34765-w


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 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.


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