Nature Communications (Nov 2022)
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,
- Evi Kostenis
Affiliations
- Tobias Benkel
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- Mirjam Zimmermann
- InterAx Biotech AG
- Julian Zeiner
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- Sergi Bravo
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- Nicole Merten
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- Victor Jun Yu Lim
- Department of Pharmaceutical Chemistry, Philipps-University of Marburg
- Edda Sofie Fabienne Matthees
- Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University of Jena
- Julia Drube
- Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University of Jena
- Elke Miess-Tanneberg
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University of Jena
- Daniela Malan
- Institute of Physiology I, Medical Faculty, University of Bonn
- Martyna Szpakowska
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH)
- Stefania Monteleone
- Department of Pharmaceutical Chemistry, Philipps-University of Marburg
- Jak Grimes
- Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham
- Zsombor Koszegi
- Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham
- Yann Lanoiselée
- Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham
- Shannon O’Brien
- Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham
- Nikoleta Pavlaki
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf
- Nadine Dobberstein
- InterAx Biotech AG
- Asuka Inoue
- Graduate School of Pharmaceutical Science, Tohoku University
- Viacheslav Nikolaev
- Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf
- Davide Calebiro
- Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham
- Andy Chevigné
- Department of Infection and Immunity, Luxembourg Institute of Health (LIH)
- Philipp Sasse
- Institute of Physiology I, Medical Faculty, University of Bonn
- Stefan Schulz
- Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University of Jena
- Carsten Hoffmann
- Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University of Jena
- Peter Kolb
- Department of Pharmaceutical Chemistry, Philipps-University of Marburg
- Maria Waldhoer
- InterAx Biotech AG
- Katharina Simon
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- Jesus Gomeza
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- Evi Kostenis
- Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn
- DOI
- https://doi.org/10.1038/s41467-022-34765-w
- Journal volume & issue
-
Vol. 13,
no. 1
pp. 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.
