Phosphoinositides (Figure 1) have been shown to mediate a large variety of important physiological functions by affecting the activity and/or localization of membrane associated proteins. The versatile inositol ring can be modified at several positions and a broad range of protein motifs bind with great specificity to the different phosphoinositides. The spatiotemporal control of protein function requires a precise regulation of phosphoinositide generation and turnover, which is facilitated by various kinases and phosphatases, as well as a high degree of compartmentalization. Depending on the position of the phosphomonoester group at the inositol ring, phosphoinositides have been shown to accumulate in specific cellular compartments. For example, phosphatidylinositol-3-phosphate (PI-3P) is an integral part of the endocytic pathway and is found to be highly enriched in early endosomes and intralumenal vesicles of multivesicular endosomes, while it is undetectable in plasma and Golgi membranes. In turn, phosphatidylinositol-4-phosphate (PI-4P) has been shown to be concentrated in Golgi membranes and phosphatidylinositol-5-phosphate (PI-5P) is involved in plasma membrane trafficking events. In addition to the cell compartment specific accumulation of phosphoinositides, it has been suggested that many of the observed physiological functions require selective enrichment of phosphoinositides in specialized membrane patches (domains). The unique physicochemical properties of these specialized domains are crucial for the correct function of a multitude of proteins and failure in the proper assembly of these superstructures has been associated with a broad range of disease states, most notably cancer.

Recent experiments from our lab furnished results consistent with a pH dependent formation of phosphoinositide enriched microdomains. The domain formation was most pronounced between approximately pH 7 – 9.5, while slightly acidic pH values (pH 4) resulted in the disintegration of the domains. This pH dependent phosphatidylcholine/ phosphoinositide demixing was observed for the gel phase (FTIR experiments) as well as for the fluid lipid phase (FRET measurements). [Details]

Figure 1: Naturally occuring phosphatidylinositol phosphates. At physiological pH, the respective phosphomonoester groups are partly protonated (average overall charge/phosphomonoester group around 1.5)