How Carvedilol activates β 2 -adrenoceptors.

Autor: Benkel T; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany.; Research Training Group 1873, University of Bonn, 53127, Bonn, Germany., Zimmermann M; InterAx Biotech AG, 5234, Villigen, Switzerland., Zeiner J; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany., Bravo S; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany., Merten N; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany., Lim VJY; Department of Pharmaceutical Chemistry, Philipps-University of Marburg, 35032, Marburg, Germany., Matthees ESF; Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University of Jena, 07745, Jena, Germany., Drube J; Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University of Jena, 07745, Jena, Germany., Miess-Tanneberg E; Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University of Jena, 07747, Jena, Germany., Malan D; Institute of Physiology I, Medical Faculty, University of Bonn, 53115, Bonn, Germany., Szpakowska M; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), L-4354, Esch-sur-Alzette, Luxembourg., Monteleone S; Department of Pharmaceutical Chemistry, Philipps-University of Marburg, 35032, Marburg, Germany., Grimes J; Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, B15 2TT, UK., Koszegi Z; Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, B15 2TT, UK., Lanoiselée Y; Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, B15 2TT, UK., O'Brien S; Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, B15 2TT, UK., Pavlaki N; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Dobberstein N; InterAx Biotech AG, 5234, Villigen, Switzerland., Inoue A; Graduate School of Pharmaceutical Science, Tohoku University, Sendai, 980-8578, Japan., Nikolaev V; Institute of Experimental Cardiovascular Research, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany., Calebiro D; Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham, B15 2TT, UK., Chevigné A; Department of Infection and Immunity, Luxembourg Institute of Health (LIH), L-4354, Esch-sur-Alzette, Luxembourg., Sasse P; Institute of Physiology I, Medical Faculty, University of Bonn, 53115, Bonn, Germany., Schulz S; Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University of Jena, 07747, Jena, Germany.; 7TM Antibodies GmbH, 07745, Jena, Germany., Hoffmann C; Institute for Molecular Cell Biology, CMB-Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University of Jena, 07745, Jena, Germany., Kolb P; Department of Pharmaceutical Chemistry, Philipps-University of Marburg, 35032, Marburg, Germany., Waldhoer M; InterAx Biotech AG, 5234, Villigen, Switzerland.; Ikherma Consulting Ltd, Hitchin, SG4 0TY, UK., Simon K; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany., Gomeza J; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany., Kostenis E; Molecular, Cellular and Pharmacobiology Section, Institute of Pharmaceutical Biology, University of Bonn, 53115, Bonn, Germany. kostenis@uni-bonn.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Nov 19; Vol. 13 (1), pp. 7109. Date of Electronic Publication: 2022 Nov 19.
DOI: 10.1038/s41467-022-34765-w
Abstrakt: 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 β 1 -adrenoceptors, arrestin-biased signalling via β 2 -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 β 2 ARs. 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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