Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs.

Autor: Pfeil EM; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany; Research Training Group 1873, University of Bonn, Bonn, Germany., Brands J; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany; Research Training Group 1873, University of Bonn, Bonn, Germany., Merten N; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Vögtle T; Institute of Experimental Biomedicine I, University Hospital Würzburg and Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany., Vescovo M; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Rick U; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Albrecht IM; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Heycke N; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Kawakami K; Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan., Ono Y; Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan., Ngako Kadji FM; Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan., Hiratsuka S; Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan., Aoki J; Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan., Häberlein F; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany; Research Training Group 1873, University of Bonn, Bonn, Germany., Matthey M; Department of Systems Physiology, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany; Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany., Garg J; Institute of Pharmacology and Toxicology, University Hospital Bonn, University of Bonn, 53127 Bonn, Germany., Hennen S; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Jobin ML; Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, 97078 Würzburg, Germany., Seier K; Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, 97078 Würzburg, Germany., Calebiro D; Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, 97078 Würzburg, Germany; Institute of Metabolism and Systems Research and Centre of Membrane Proteins and Receptors, University of Birmingham, B15 2TT Birmingham, UK., Pfeifer A; Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany., Heinemann A; Division of Pharmacology, Otto-Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, 8010 Graz, Austria., Wenzel D; Department of Systems Physiology, Medical Faculty, Ruhr University Bochum, 44801 Bochum, Germany; Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany., König GM; Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany., Nieswandt B; Institute of Experimental Biomedicine I, University Hospital Würzburg and Rudolf Virchow Center, University of Würzburg, 97080 Würzburg, Germany., Fleischmann BK; Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Venusberg-Campus 1, 53127 Bonn, Germany., Inoue A; Graduate School of Pharmaceutical Science, Tohoku University, Sendai 980-8578, Japan., Simon K; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany. Electronic address: ksimon1@uni-bonn.de., Kostenis E; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany. Electronic address: kostenis@uni-bonn.de.
Jazyk: angličtina
Zdroj: Molecular cell [Mol Cell] 2020 Dec 17; Vol. 80 (6), pp. 940-954.e6. Date of Electronic Publication: 2020 Nov 16.
DOI: 10.1016/j.molcel.2020.10.027
Abstrakt: Mechanisms that control mobilization of cytosolic calcium [Ca 2+ ] i are key for regulation of numerous eukaryotic cell functions. One such paradigmatic mechanism involves activation of phospholipase Cβ (PLCβ) enzymes by G protein βγ subunits from activated Gα i -Gβγ heterotrimers. Here, we report identification of a master switch to enable this control for PLCβ enzymes in living cells. We find that the Gα i -Gβγ-PLCβ-Ca 2+ signaling module is entirely dependent on the presence of active Gα q . If Gα q is pharmacologically inhibited or genetically ablated, Gβγ can bind to PLCβ but does not elicit Ca 2+ signals. Removal of an auto-inhibitory linker that occludes the active site of the enzyme is required and sufficient to empower "stand-alone control" of PLCβ by Gβγ. This dependence of Gi-Gβγ-Ca 2+ on Gα q places an entire signaling branch of G-protein-coupled receptors (GPCRs) under hierarchical control of Gq and changes our understanding of how Gi-GPCRs trigger [Ca 2+ ] i via PLCβ enzymes.
Competing Interests: Declaration of Interests The authors declare no competing interests.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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