The preferential localization of SM and cholesterol within Lo phases is well-established . In contrast, little is known about the involvement of phosphatidylinositol (PI), and its phosphorylated derivatives, in Lo and Ld phases. The most abundant PI(4,5)P 2 species in brain extracts feature 18:0 and 20:4 acyl chains, giving this lipid unique properties . The straight, saturated 18:0 chain closely aligns with cholesterol's structure, promoting tight packing and order within membranes. This is further enhanced by forming hydrogen bonds with cholesterol's hydroxyl group . Conversely, the highly unsaturated 20:4 chain introduces flexibility and disorder, favoring disordered regions and they might promote interdigitation with the outer plasma membrane leaflet. Detergent-resistant membrane (DRM) experiments revealed that PI(4,5)P 2 is enriched in ordered regions. Notably, cholesterol depletion using methyl-beta-cyclodextrin causes PI(4,5)P 2 to redistribute into disordered regions . However, DRM assays are often criticized for potential artifact detergents introduced during the procedure. Alternative studies using Giant Unilamellar Vesicles (GUVs) and Lo/Ld-directed peptides have shown PI(4,5)P 2 to be more homogeneously distributed across the membrane . Interestingly, this study also noted that PI(4,5)P 2 in Lo regions undergoes rapid turnover, being converted to diacylglycerol (DAG) and inositol trisphosphate (IP3) and replenished at a faster rate compared to PI(4,5)P 2 in Ld regions. The reported data suggest that PI(4,5)P 2 in Lo regions functions as a dynamic pool, regulating the concentrations of other PI derivatives through the activity of PI kinases and phosphatases. These enzymes are also reported to localize within Lo regions (Van Den Bogaart et al. 2011; J. Wang and Richards 2012), further supporting the functional interplay between PI(4,5)P 2 and Lo phase.