@article{96166f84558349a4a8b021cbe8627449,
title = "Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs",
abstract = "Mechanisms that control mobilization of cytosolic calcium [Ca2+]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 Gαi-Gβγ heterotrimers. Here, we report identification of a master switch to enable this control for PLCβ enzymes in living cells. We find that the Gαi-Gβγ-PLCβ-Ca2+ signaling module is entirely dependent on the presence of active Gαq. If Gαq is pharmacologically inhibited or genetically ablated, Gβγ can bind to PLCβ but does not elicit Ca2+ 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-Ca2+ on Gαq 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 [Ca2+]i via PLCβ enzymes.",
keywords = "Ca signaling, FR900359, GPCR, GPR17, Gi, Gq, PTX, heterotrimeric G protein, phospholipase Cβ, real-time BRET-based IP biosensor",
author = "Pfeil, {Eva Marie} and Julian Brands and Nicole Merten and Timo V{\"o}gtle and Maddalena Vescovo and Ulrike Rick and Albrecht, {Ina Maria} and Nina Heycke and Kouki Kawakami and Yuki Ono and {Ngako Kadji}, {Francois Marie} and Suzune Hiratsuka and Junken Aoki and Felix H{\"a}berlein and Michaela Matthey and Jaspal Garg and Stephanie Hennen and Jobin, {Marie Lise} and Kerstin Seier and Davide Calebiro and Alexander Pfeifer and Akos Heinemann and Daniela Wenzel and K{\"o}nig, {Gabriele M.} and Bernhard Nieswandt and Fleischmann, {Bernd K.} and Asuka Inoue and Katharina Simon and Evi Kostenis",
note = "Funding Information: This work was funded by the Deutsche Forschungsgemeinschaft (DFG) (German Research Foundation) grants 214362475/GRK1873/2 and WE 4461/2-1 (to E.K., D.W., and B.F.), KO 1582/10-1 and KO 1582/10-2 (to E.K.), KO 902/17-1 and KO 902/17-2 (to G.M.K.), the PRIME ( JP19gm5910013 to A.I.) and the LEAP ( JP19gm0010004 to A.I. and J.A.) from the Japan Agency for Medical Research and Development (AMED), JSPS KAKENHI grant ( 17K08264 to A.I.) from Japan Society for the Promotion of Science , and the Sonderforschungsbereich/Transregio 166–Project C1 (to D.C.). D.C. is supported by a Wellcome Trust Senior Research Fellowship. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = dec,
day = "17",
doi = "10.1016/j.molcel.2020.10.027",
language = "English",
volume = "80",
pages = "940--954.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}