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

Eva Marie Pfeil, Julian Brands, Nicole Merten, Timo Vögtle, Maddalena Vescovo, Ulrike Rick, Ina Maria Albrecht, Nina Heycke, Kouki Kawakami, Yuki Ono, Francois Marie Ngako Kadji, Suzune Hiratsuka, Junken Aoki, Felix Häberlein, Michaela Matthey, Jaspal Garg, Stephanie Hennen, Marie Lise Jobin, Kerstin Seier, Davide CalebiroAlexander Pfeifer, Akos Heinemann, Daniela Wenzel, Gabriele M. König, Bernhard Nieswandt, Bernd K. Fleischmann, Asuka Inoue, Katharina Simon, Evi Kostenis

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)940-954.e6
JournalMolecular Cell
Volume80
Issue number6
DOIs
Publication statusPublished - 2020 Dec 17
Externally publishedYes

Keywords

  • Ca signaling
  • FR900359
  • GPCR
  • GPR17
  • Gi
  • Gq
  • PTX
  • heterotrimeric G protein
  • phospholipase Cβ
  • real-time BRET-based IP biosensor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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