磷脂肌醇（3,4,5）三磷酸酯（PIP3）是一种与许多细胞信号通路有关的贴附在质膜上的信号磷脂，控制着关键的细胞过程和行为，包括细胞骨架重塑、代谢、趋化和细胞凋亡。因此，缺陷的PIP3信号与各种疾病有关，包括癌症、糖尿病、肥胖和心血管疾病。当G蛋白偶联受体（GPCRs）或受体酪氨酸激酶（RTKs）被激活时，磷脂肌醇-3-激酶（PI3Ks）磷酸化磷脂肌醇（4,5）双磷酸酯（PIP2），生成PIP3。尽管机制尚不清楚，在GPCR激活时产生的PIP3在几分钟内减弱，表明紧密的时间调节。我们的数据显示，当全球激活GPCRs时，G蛋白的亚细胞重分布控制着这种PIP3的减弱，而局部GPCR激活引起持续的亚细胞PIP3。有趣的是，观察到的PIP3减弱依赖于Gγ亚型。考虑到不同细胞-组织特异性Gγ表达谱，我们的发现不仅展示了GPCR诱导的PIP3响应如何根据细胞中GPCR活性梯度进行调节，而且展示了细胞如何对外部刺激的时空变异做出不同的反应。 © 2023。作者。

Phosphatidylinositol (3,4,5) trisphosphate (PIP3) is a plasma membrane-bound signaling phospholipid involved in many cellular signaling pathways that control crucial cellular processes and behaviors, including cytoskeleton remodeling, metabolism, chemotaxis, and apoptosis. Therefore, defective PIP3 signaling is implicated in various diseases, including cancer, diabetes, obesity, and cardiovascular diseases. Upon activation by G protein-coupled receptors (GPCRs) or receptor tyrosine kinases (RTKs), phosphoinositide-3-kinases (PI3Ks) phosphorylate phosphatidylinositol (4,5) bisphosphate (PIP2), generating PIP3. Though the mechanisms are unclear, PIP3 produced upon GPCR activation attenuates within minutes, indicating a tight temporal regulation. Our data show that subcellular redistributions of G proteins govern this PIP3 attenuation when GPCRs are activated globally, while localized GPCR activation induces sustained subcellular PIP3. Interestingly the observed PIP3 attenuation was Gγ subtype-dependent. Considering distinct cell-tissue-specific Gγ expression profiles, our findings not only demonstrate how the GPCR-induced PIP3 response is regulated depending on the GPCR activity gradient across a cell, but also show how diversely cells respond to spatial and temporal variability of external stimuli.© 2023. The Author(s).