Molecular Cell
Volume 80, Issue 6, 17 December 2020, Pages 940-954.e6
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Article
Heterotrimeric G Protein Subunit Gαq Is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs

https://doi.org/10.1016/j.molcel.2020.10.027Get rights and content
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Highlights

  • Newly delineated mechanism of Ca2+ signaling by Gi-G-protein-coupled receptors

  • Paradigmatic Gi-Gβγ-Ca2+ signals require Gαq subunit in living cells

  • Relieving auto-inhibition of PLCβ empowers Gβγ-Ca2+ signaling in the absence of Gαq

Summary

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

GPCR
heterotrimeric G protein
Gq
Gi
phospholipase Cβ
real-time BRET-based IP3 biosensor
Ca2+ signaling
FR900359
PTX
GPR17

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12

These authors contributed equally

13

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