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 Vogtle; Maddalena Vescovo; Ulrike Rich; Ina-Maria Albrecht; Nina Heycke; Kouki Kawakami; Yuki Ono; Francois Marie Ngako Kadji; Suzune Hiratsuka; Junken Aoki; Felix Haberlein; Michaela Matthey; Jaspal Garg; Stephanie Hennen; Marie-Lise Jobin; Kerstin Seier; Davide Calebiro; Alexander Pfeifer; Akos Heinemann; Daniela Wenzel; Gabriele  Konig; Bernhard Nieswandt; Bernd Fleischmann; Asuka Inoue; Anna Katharina Simon; Evi Kostenis

doi:10.1016/j.molcel.2020.10.027

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 Vogtle, Maddalena Vescovo, Ulrike Rich, Ina-Maria Albrecht, Nina Heycke, Kouki Kawakami, Yuki Ono, Francois Marie Ngako Kadji, Suzune Hiratsuka, Junken Aoki, Felix Haberlein, Michaela Matthey, Jaspal Garg, Stephanie Hennen, Marie-Lise Jobin, Kerstin Seier, Davide CalebiroAlexander Pfeifer, Akos Heinemann, Daniela Wenzel, Gabriele Konig, Bernhard Nieswandt, Bernd Fleischmann, Asuka Inoue, Anna Katharina Simon, Evi Kostenis

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	940-954.e6
Journal	Molecular Cell
Volume	80
Issue number	6
Early online date	16 Nov 2020
DOIs	https://doi.org/10.1016/j.molcel.2020.10.027
Publication status	Published - 17 Dec 2020

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Pfeil, E. M., Brands, J., Merten, N., Vogtle, T., Vescovo, M., Rich, U., Albrecht, I-M., Heycke, N., Kawakami, K., Ono, Y., Kadji, F. M. N., Hiratsuka, S., Aoki, J., Haberlein, F., Matthey, M., Garg, J., Hennen, S., Jobin, M-L., Seier, K., ... Kostenis, E. (2020). Heterotrimeric G protein subunit Gαq is a master switch for Gβγ-mediated calcium mobilization by Gi-coupled GPCRs. Molecular Cell, 80(6), 940-954.e6. Advance online publication. https://doi.org/10.1016/j.molcel.2020.10.027

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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.",

author = "Pfeil, {Eva Marie} and Julian Brands and Nicole Merten and Timo Vogtle and Maddalena Vescovo and Ulrike Rich and Ina-Maria Albrecht and Nina Heycke and Kouki Kawakami and Yuki Ono and Kadji, {Francois Marie Ngako} and Suzune Hiratsuka and Junken Aoki and Felix Haberlein and Michaela Matthey and Jaspal Garg and Stephanie Hennen and Marie-Lise Jobin and Kerstin Seier and Davide Calebiro and Alexander Pfeifer and Akos Heinemann and Daniela Wenzel and Gabriele Konig and Bernhard Nieswandt and Bernd Fleischmann and Asuka Inoue and Simon, {Anna Katharina} and Evi Kostenis",

year = "2020",

month = dec,

day = "17",

doi = "10.1016/j.molcel.2020.10.027",

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Pfeil, EM, Brands, J, Merten, N, Vogtle, T, Vescovo, M, Rich, U, Albrecht, I-M, Heycke, N, Kawakami, K, Ono, Y, Kadji, FMN, Hiratsuka, S, Aoki, J, Haberlein, F, Matthey, M, Garg, J, Hennen, S, Jobin, M-L, Seier, K, Calebiro, D, Pfeifer, A, Heinemann, A, Wenzel, D, Konig, G, Nieswandt, B, Fleischmann, B, Inoue, A, Simon, AK & Kostenis, E 2020, 'Heterotrimeric G protein subunit Gαq is a master switch for Gβγ-mediated calcium mobilization by Gi-coupled GPCRs', Molecular Cell, vol. 80, no. 6, pp. 940-954.e6. https://doi.org/10.1016/j.molcel.2020.10.027

TY - JOUR

T1 - Heterotrimeric G protein subunit Gαq is a master switch for Gβγ-mediated calcium mobilization by Gi-coupled GPCRs

AU - Pfeil, Eva Marie

AU - Brands, Julian

AU - Merten, Nicole

AU - Vogtle, Timo

AU - Vescovo, Maddalena

AU - Rich, Ulrike

AU - Albrecht, Ina-Maria

AU - Heycke, Nina

AU - Kawakami, Kouki

AU - Ono, Yuki

AU - Kadji, Francois Marie Ngako

AU - Hiratsuka, Suzune

AU - Aoki, Junken

AU - Haberlein, Felix

AU - Matthey, Michaela

AU - Garg, Jaspal

AU - Hennen, Stephanie

AU - Jobin, Marie-Lise

AU - Seier, Kerstin

AU - Calebiro, Davide

AU - Pfeifer, Alexander

AU - Heinemann, Akos

AU - Wenzel, Daniela

AU - Konig, Gabriele

AU - Nieswandt, Bernhard

AU - Fleischmann, Bernd

AU - Inoue, Asuka

AU - Simon, Anna Katharina

AU - Kostenis, Evi

PY - 2020/12/17

Y1 - 2020/12/17

N2 - 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.

AB - 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.

U2 - 10.1016/j.molcel.2020.10.027

DO - 10.1016/j.molcel.2020.10.027

M3 - Article

SN - 1097-2765

VL - 80

SP - 940-954.e6

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Heterotrimeric G protein subunit Gαq is a master switch for Gβγ-mediated calcium mobilization by Gi-coupled GPCRs

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