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

Standard

How Carvedilol activates β2-adrenoceptors. / Benkel, Tobias; Zimmermann, Mirjam; Zeiner, Julian; Bravo, Sergi; Merten, Nicole; Lim, Victor Jun Yu; Matthees, Edda Sofie Fabienne; Drube, Julia; Miess-Tanneberg, Elke; Malan, Daniela; Szpakowska, Martyna; Monteleone, Stefania; Grimes, Jak; Koszegi, Zsombor; Lanoiselée, Yann; O'Brien, Shannon; Pavlaki, Nikoleta; Dobberstein, Nadine; Inoue, Asuka; Nikolaev, Viacheslav; Calebiro, Davide; Chevigné, Andy; Sasse, Philipp; Schulz, Stefan; Hoffmann, Carsten; Kolb, Peter; Waldhoer, Maria; Simon, Katharina; Gomeza, Jesus; Kostenis, Evi.

in: NAT COMMUN, Jahrgang 13, Nr. 1, 7109, 19.11.2022.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

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', NAT COMMUN, Jg. 13, Nr. 1, 7109. https://doi.org/10.1038/s41467-022-34765-w

APA

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. NAT COMMUN, 13(1), [7109]. https://doi.org/10.1038/s41467-022-34765-w

Vancouver

Benkel T, Zimmermann M, Zeiner J, Bravo S, Merten N, Lim VJY et al. How Carvedilol activates β2-adrenoceptors. NAT COMMUN. 2022 Nov 19;13(1). 7109. https://doi.org/10.1038/s41467-022-34765-w

Bibtex

@article{bac42557f1b84f1dbf181b373718d88b,

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'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.",

keywords = "Humans, Carvedilol/pharmacology, Adrenergic beta-Antagonists/pharmacology, Receptors, Adrenergic, beta-2/genetics, Myocardial Infarction/drug therapy",

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'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 = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = nov,

day = "19",

doi = "10.1038/s41467-022-34765-w",

language = "English",

volume = "13",

journal = "NAT COMMUN",

issn = "2041-1723",

publisher = "NATURE PUBLISHING GROUP",

number = "1",

}

RIS

TY - JOUR

T1 - How Carvedilol activates β2-adrenoceptors

AU - Benkel, Tobias

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

AU - Malan, Daniela

AU - Szpakowska, Martyna

AU - Monteleone, Stefania

AU - Grimes, Jak

AU - Koszegi, Zsombor

AU - Lanoiselée, Yann

AU - O'Brien, Shannon

AU - Pavlaki, Nikoleta

AU - Dobberstein, Nadine

AU - Inoue, Asuka

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

PY - 2022/11/19

Y1 - 2022/11/19

N2 - 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.

AB - 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.

KW - Humans

KW - Carvedilol/pharmacology

KW - Adrenergic beta-Antagonists/pharmacology

KW - Receptors, Adrenergic, beta-2/genetics

KW - Myocardial Infarction/drug therapy

U2 - 10.1038/s41467-022-34765-w

DO - 10.1038/s41467-022-34765-w

M3 - SCORING: Journal article

C2 - 36402762

VL - 13

JO - NAT COMMUN

JF - NAT COMMUN

SN - 2041-1723

IS - 1

M1 - 7109

ER -