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 Gα_i-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_i-Gβγ-PLCβ-Ca²⁺ signaling module is entirely dependent on the presence of active Gα_q. If Gα_q 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 Gα_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 PLCβ enzymes.

控制细胞质钙[Ca ²⁺ ] _i动员的机制是调节许多真核细胞功能的关键。一种这样的例证机制涉及通过G蛋白βγ亚基磷脂酶Cβ（PLCβ）的酶的活化从活化Gα_我-Gβγ异源三聚。在这里，我们报告了一个主开关的识别，该开关可以对活细胞中的PLCβ酶进行控制。我们发现，Gα_我-Gβγ-PLCβ钙²⁺信令模块完全依赖于活性Gα的存在_q。如果Gα _q是药理学抑制或遗传消融，Gβγ可以结合PLCβ但不引起的Ca ²⁺信号。需要去除封闭酶的活性位点的自抑制接头，并且足以使Gβγ“独立控制”PLCβ。此GI-Gβγ钙依赖性²⁺对Gα _q的Gq的分级控制下放置的G蛋白偶联受体（GPCR）的整个信令分支和改变了我们如何GI-GPCR的触发的[Ca理解²⁺ ]_我通过PLCβ酶。