Figure 3. The signal PLC transduction pathway is coupled to PI re-synthesis to maintain the PIPn pool.

The activation of PLC (phospholipase C) in response to GPCR agonists (G protein-coupled receptors) induces the cleavage of PI(4,5)P₂, generating DG (diacylglycerol) and IP₃ (inositol 1,4,5-trisphosphate), which leads to the release of Ca²⁺ from intracellular stores and the activation of PKC (protein kinase C), respectively. The drop in the total PIPn pool caused by PI(4,5)P₂ hydrolysis is compensated by the activation of PI synthesis. It has been proposed that this PI re-synthesis involves a closed ‘PI cycle’ (red arrows), where the DG generated by the hydrolysis of PI(4,5)P₂ is selectively recycled back into PI to maintain the total PIPn pool. This process involves the transport of the generated DG and/or PA from the PM (plasma membrane) to the ER (endoplasmic reticulum), where it can be utilized by PI synthesis enzymes CDS and PIS. This cycle could be spatially confined to PM-ER contact sites, where LTPs (lipid transfer proteins) transport the lipid intermediates between membranes (dotted lines). The C38:4 backbone could facilitate the PI cycle by providing molecular identity with the DG and PA molecules, preventing their consumption by other biosynthetic pathways as well as the utilization of intermediates from other origins, such as PA generated from PC via PLD (phospholipase D).