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.

磷脂酰肌醇 (3,4,5) 三磷酸 (PIP3) 是一种质膜结合信号磷脂，参与许多控制关键细胞过程和行为的细胞信号传导途径，包括细胞骨架重塑、代谢、趋化性和细胞凋亡。因此，PIP3 信号传导缺陷与多种疾病有关，包括癌症、糖尿病、肥胖和心血管疾病。被 G 蛋白偶联受体 (GPCR) 或受体酪氨酸激酶 (RTK) 激活后，磷酸肌醇 3-激酶 (PI3K) 磷酸化磷脂酰肌醇 (4,5) 二磷酸 (PIP2)，生成 PIP3。尽管机制尚不清楚，但 GPCR 激活后产生的 PIP3 在几分钟内减弱，表明严格的时间调节。我们的数据表明，当 GPCR 全局激活时，G 蛋白的亚细胞重新分布控制这种 PIP3 衰减，而局部 GPCR 激活则诱导持续的亚细胞 PIP3。有趣的是，观察到的 PIP3 衰减是 Gγ 亚型依赖性的。考虑到不同的细胞组织特异性 Gγ 表达谱，我们的研究结果不仅证明了 GPCR 诱导的 PIP3 反应如何根据细胞内 GPCR 活性梯度进行调节，而且还表明细胞对外部刺激的空间和时间变异性的反应如何不同。