How Carvedilol activates β2-adrenoceptors

Tobias Benkel, Mirjam Zimmermann, Julian Zeiner, Sergi Bravo, Nicole Merten, Victor Jun Yu Lim, Edda Sofie Fabienne Matthees, Julia Drube, Elke Miess-Tanneberg, Daniela Malan, Martyna Szpakowska, Stefania Monteleone, Jak Grimes, Zsombor Koszegi, Yann Lanoiselée, Shannon O’Brien, Nikoleta Pavlaki, Nadine Dobberstein, Asuka Inoue, Viacheslav Nikolaev, Davide Calebiro, Andy Chevigné, Philipp Sasse, Stefan Schulz, Carsten Hoffmann, Peter Kolb, Maria Waldhoer, Katharina Simon, Jesus Gomeza and Evi Kostenis ()
Additional contact information
Tobias Benkel: University of Bonn
Mirjam Zimmermann: InterAx Biotech AG
Julian Zeiner: University of Bonn
Sergi Bravo: University of Bonn
Nicole Merten: University of Bonn
Victor Jun Yu Lim: Philipps-University of Marburg
Edda Sofie Fabienne Matthees: Jena University Hospital, Friedrich Schiller University of Jena
Julia Drube: Jena University Hospital, Friedrich Schiller University of Jena
Elke Miess-Tanneberg: Jena University Hospital, Friedrich Schiller University of Jena
Daniela Malan: University of Bonn
Martyna Szpakowska: Luxembourg Institute of Health (LIH)
Stefania Monteleone: Philipps-University of Marburg
Jak Grimes: University of Birmingham
Zsombor Koszegi: University of Birmingham
Yann Lanoiselée: University of Birmingham
Shannon O’Brien: University of Birmingham
Nikoleta Pavlaki: University Medical Center Hamburg-Eppendorf
Nadine Dobberstein: InterAx Biotech AG
Asuka Inoue: Tohoku University
Viacheslav Nikolaev: University Medical Center Hamburg-Eppendorf
Davide Calebiro: University of Birmingham
Andy Chevigné: Luxembourg Institute of Health (LIH)
Philipp Sasse: University of Bonn
Stefan Schulz: Jena University Hospital, Friedrich Schiller University of Jena
Carsten Hoffmann: Jena University Hospital, Friedrich Schiller University of Jena
Peter Kolb: Philipps-University of Marburg
Maria Waldhoer: InterAx Biotech AG
Katharina Simon: University of Bonn
Jesus Gomeza: University of Bonn
Evi Kostenis: University of Bonn

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34765-w

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DOI: 10.1038/s41467-022-34765-w

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