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 [Ca] 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 Gα-Gβγ heterotrimers. Here, we report identification of a master switch to enable this control for PLCβ enzymes in living cells. We find that the Gα-Gβγ-PLCβ-Ca signaling module is entirely dependent on the presence of active Gα. If Gα is pharmacologically inhibited or genetically ablated, Gβγ can bind to PLCβ but does not elicit Ca 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-Ca on Gα 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 [Ca] via PLCβ enzymes.