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

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. Dependence on Gαq of Gi-Gβγ-Ca2+ is a mechanism placing 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.