Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH, 43606, USA.
Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, Saint Louis, MO, 63103, USA.
Sci Rep. 2023 Feb 16;13(1):2771. doi: 10.1038/s41598-023-29639-0.
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）是一种结合在质膜上的信号磷脂，参与许多控制关键细胞过程和行为的细胞信号通路，包括细胞骨架重塑、代谢、趋化性和细胞凋亡。因此，PIP3 信号的缺陷与各种疾病有关，包括癌症、糖尿病、肥胖症和心血管疾病。当被 G 蛋白偶联受体（GPCRs）或受体酪氨酸激酶（RTKs）激活时，磷酸肌醇-3-激酶（PI3Ks）磷酸化磷脂酰肌醇（4,5）二磷酸（PIP2），生成 PIP3。虽然机制尚不清楚，但当 GPCR 被全局激活时，几分钟内产生的 PIP3 就会减弱，这表明存在严格的时间调控。我们的数据表明，当 GPCR 被激活时，G 蛋白的亚细胞重分布控制着这种 PIP3 的衰减，而局部 GPCR 的激活则诱导持续的亚细胞 PIP3。有趣的是，观察到的 PIP3 衰减与 Gγ 亚基的依赖性有关。考虑到不同细胞组织中特定的 Gγ 表达模式，我们的发现不仅展示了细胞内 GPCR 活性梯度如何调节 GPCR 诱导的 PIP3 反应，还展示了细胞如何对外部刺激的时空变化做出多样化的反应。
