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

doi:10.1038/s41467-022-34765-w

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 NikolaevDavide Calebiro, Andy Chevigné, Philipp Sasse, Stefan Schulz, Carsten Hoffmann, Peter Kolb, Maria Waldhoer, Katharina Simon, Jesus Gomeza, Evi Kostenis^*

^*Corresponding author for this work

Metabolism and Systems Science

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

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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.

Original language	English
Article number	7109
Number of pages	20
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	19 Nov 2022
DOIs	https://doi.org/10.1038/s41467-022-34765-w
Publication status	Published - Dec 2022

Bibliographical note

Funding Information:
We thank Ulrike Rick and Kimberly Harisch for excellent assistance. This study was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) 290847012/FOR2372 to E.K. and Heisenberg professorships KO4095/4-1 and KO4095/5-1 to P.K. T.B. was a member of the DFG-funded Research Training Group RTG1873 (214362475/GRK1873/2). A.C. and M.S. were supported by the Luxembourg National Research Fund (INTER/FWO “Nanokine” grant 15/10358798, INTER/FNRS grants 20/15084569, and PoC “Megakine” 19/14209621), F.R.S-FNRS-Télévie (7.8504.20). D.C. was supported by a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z). This article is based upon work from COST Action ERNEST (CA18133), supported by COST (European Cooperation in Science and Technology, www.cost.eu ).

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

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Cite this

Benkel, T., Zimmermann, M., Zeiner, J., Bravo, S., Merten, N., Lim, V. J. Y., Matthees, E. S. F., 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., ... Kostenis, E. (2022). How Carvedilol activates β₂-adrenoceptors. Nature Communications, 13(1), Article 7109. https://doi.org/10.1038/s41467-022-34765-w

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title = "How Carvedilol activates β2-adrenoceptors",

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{\textquoteright}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.",

author = "Tobias Benkel and Mirjam Zimmermann and Julian Zeiner and Sergi Bravo and Nicole Merten and Lim, {Victor Jun Yu} and Matthees, {Edda Sofie Fabienne} and Julia Drube and Elke Miess-Tanneberg and Daniela Malan and Martyna Szpakowska and Stefania Monteleone and Jak Grimes and Zsombor Koszegi and Yann Lanoisel{\'e}e and Shannon O{\textquoteright}Brien and Nikoleta Pavlaki and Nadine Dobberstein and Asuka Inoue and Viacheslav Nikolaev and Davide Calebiro and Andy Chevign{\'e} and Philipp Sasse and Stefan Schulz and Carsten Hoffmann and Peter Kolb and Maria Waldhoer and Katharina Simon and Jesus Gomeza and Evi Kostenis",

note = "Funding Information: We thank Ulrike Rick and Kimberly Harisch for excellent assistance. This study was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) 290847012/FOR2372 to E.K. and Heisenberg professorships KO4095/4-1 and KO4095/5-1 to P.K. T.B. was a member of the DFG-funded Research Training Group RTG1873 (214362475/GRK1873/2). A.C. and M.S. were supported by the Luxembourg National Research Fund (INTER/FWO “Nanokine” grant 15/10358798, INTER/FNRS grants 20/15084569, and PoC “Megakine” 19/14209621), F.R.S-FNRS-T{\'e}l{\'e}vie (7.8504.20). D.C. was supported by a Wellcome Trust Senior Research Fellowship (212313/Z/18/Z). This article is based upon work from COST Action ERNEST (CA18133), supported by COST (European Cooperation in Science and Technology, www.cost.eu ). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

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Benkel, T, Zimmermann, M, Zeiner, J, Bravo, S, Merten, N, Lim, VJY, Matthees, ESF, 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 2022, 'How Carvedilol activates β₂-adrenoceptors', Nature Communications, vol. 13, no. 1, 7109. https://doi.org/10.1038/s41467-022-34765-w

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AU - Zimmermann, Mirjam

AU - Zeiner, Julian

AU - Bravo, Sergi

AU - Merten, Nicole

AU - Lim, Victor Jun Yu

AU - Matthees, Edda Sofie Fabienne

AU - Drube, Julia

AU - Miess-Tanneberg, Elke

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AU - Nikolaev, Viacheslav

AU - Calebiro, Davide

AU - Chevigné, Andy

AU - Sasse, Philipp

AU - Schulz, Stefan

AU - Hoffmann, Carsten

AU - Kolb, Peter

AU - Waldhoer, Maria

AU - Simon, Katharina

AU - Gomeza, Jesus

AU - Kostenis, Evi

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