There are many isoforms of phospholipase C (PLC), the enzyme that cleaves phosphatidylinositol 4,5 diphosphate (PIP2). PLC-β isoforms are activated by Gαq in response to activation of G protein-coupled receptors (GPCRs). The regulation of the PLC-δ isoforms is less well understood. Guo et al. present evidence to suggest that PLC-β2 maintains PLC-δ1 in an inactive state and that increased concentrations of the Gβγ disrupt the interaction between the two proteins, allowing PLC-δ1 to become active. This provides one model to explain how PLC-δ amplifies calcium signals initiated by PLC-β. Using a fluorescent probe covalently attached to PLC-β2, a direct association between PLC-β2 and PLC-δ1 was detected in vitro, and the affinity of the interaction was increased if the enzymes were immobilized on membranes. In vitro enzymatic activity was less than additive when both isoforms were present, suggesting that one or both enzymes were being inhibited. Using several different assay conditions, the authors determined that the activity of PLC-δ1 was inhibited by the presence of PLC-β2. The addition of Gβγ to the mixture of PLC-β2 and PLC-δ1 disrupted complex formation between the two enzymes in vitro and abolished inhibition of enzyme activity when the enzymes were mixed. Experiments with endogenously expressed PLC-β2 and PLC-δ1, as well as with cells transfected with versions of the proteins for bimolecular fluorescence complementation (BiFC), indicated that both proteins localized at the plasma membrane in unstimulated cells. In the BiFC experiment, stimulation of the cells with acetylcholine, which activates muscarinic GPCRs, decreased the enzymes' interaction. In the transfected cells, inhibition of Gα with pertussis toxin, which allows Gβγ to accumulate, disrupted the interaction between PLC-β2 and PLC-δ1, and this disruption by increasing concentrations of Gβγ was reproducible in isolated membrane preparations from the BiFC-transfected cells. Thus, it appears that in cells expressing both PLC-β2 and PLC-δ1, PLC-β2 maintains PLC-δ1 in an inactive state, and this inhibition is relieved by the Gβγ subunits of the G proteins activated in response to GPCR stimulation. Thus G proteins have a dual role in producing a calcium signal: Gα stimulates PLC-β2 and Gβγ disrupts the PLC-β2 and PLC-δ1 complex, allowing PLC-δ1 to enhance the signal.