A molecular mechanism to diversify Ca 2+ signaling downstream of Gs protein-coupled receptors.

Autor: Brands J; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany.; Research Training Group 1873, University of Bonn, Bonn, Germany., Bravo S; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany., Jürgenliemke L; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany.; Research Training Group 2873, University of Bonn, Bonn, Germany., Grätz L; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Schihada H; Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany., Frechen F; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Alenfelder J; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany., Pfeil C; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany.; Research Training Group 1873, University of Bonn, Bonn, Germany.; Amsterdam Institute for Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, Amsterdam, Netherlands., Ohse PG; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany., Hiratsuka S; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan., Kawakami K; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.; Komaba Institute for Science, The University of Tokyo, Meguro, Tokyo, 153-8505, Japan., Schmacke LC; Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany., Heycke N; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany., Inoue A; Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan.; Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, 606-8501, Japan., König G; Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany., Pfeifer A; Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany., Wachten D; Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany., Schulte G; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden., Steinmetzer T; Department of Pharmaceutical Chemistry, Philipps-University Marburg, Marburg, Germany., Watts VJ; Department of Medicinal Chemistry and Molecular Pharmacology, Purdue Institute of Drug Discovery, Purdue University, West Lafayette, IN, USA., Gomeza J; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany., Simon K; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany.; Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35131, Padova, Italy., Kostenis E; Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Bonn, Germany. kostenis@uni-bonn.de.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Sep 03; Vol. 15 (1), pp. 7684. Date of Electronic Publication: 2024 Sep 03.
DOI: 10.1038/s41467-024-51991-6
Abstrakt: A long-held tenet in inositol-lipid signaling is that cleavage of membrane phosphoinositides by phospholipase Cβ (PLCβ) isozymes to increase cytosolic Ca 2+ in living cells is exclusive to Gq- and Gi-sensitive G protein-coupled receptors (GPCRs). Here we extend this central tenet and show that Gs-GPCRs also partake in inositol-lipid signaling and thereby increase cytosolic Ca 2+ . By combining CRISPR/Cas9 genome editing to delete Gα s , the adenylyl cyclase isoforms 3 and 6, or the PLCβ1-4 isozymes, with pharmacological and genetic inhibition of Gq and G11, we pin down Gs-derived Gβγ as driver of a PLCβ2/3-mediated cytosolic Ca 2+ release module. This module does not require but crosstalks with Gα s -dependent cAMP, demands Gα q to release PLCβ3 autoinhibition, but becomes Gq-independent with mutational disruption of the PLCβ3 autoinhibited state. Our findings uncover the key steps of a previously unappreciated mechanism utilized by mammalian cells to finetune their calcium signaling regulation through Gs-GPCRs.
(© 2024. The Author(s).)
Databáze: MEDLINE
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