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 C beta (PLC beta) enzymes by G protein beta gamma subunits from activated G alpha(i)-G beta gamma heterotrimers. Here, we report identification of a master switch to enable this control for PLC beta enzymes in living cells. We find that the G alpha(i)-G beta gamma-PLC beta-Ca2+ signaling module is entirely dependent on the presence of active G alpha(q). If G alpha(q) is pharmacologically inhibited or genetically ablated, G beta gamma can bind to PLC beta 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 PLC beta by G beta gamma. This dependence of Gi-G beta gamma-Ca2+ on G alpha(q) 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 PLC beta enzymes.