Molecular regulation of GPCR-G-protein-governed PIP3 generation and its adaptation

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 disease driving processes, including cancer metastasis, 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. Interestingly, though the mechanisms are unclear, PIP3 produced upon GPCR activation attenuates within minutes, indicating a tight temporal regulation. Our data show the subcellular redistributions of G proteins govern this PIP3 attenuation in the presence of sustained receptor stimulation, and thus meet the definition of signaling adaptation. Interestingly the observed adaptation of PIP3 was G{gamma} subtype-dependent. Considering distinct cell-tissue-specific G{gamma} expression profiles, our findings not only demonstrate how the GPCR-induced PIP3 response is adapted but also show how diversely this adaptation process is regulated by the dominant G{gamma}s of a cell.