Inositol phosphates and cell activation

The formation of inositol phosphates is a good measure of the activity of PLC. Within seconds of addition of fMet-Leu-Phe to neutrophils, Ins 1,4,5-P3 formation is detected, and levels of this compound increase for about 20-30 s, falling to their original levels within 2 min of stimulation. It is likely that this decrease in Ins 1,4,5-P3 occurs because it is phosphorylated to inositol 1,3,4,5-tetrakisphosphate (Ins 1,3,4,5-P4) and then subsequently dephosphorylated to inositol 1,3,4-trisphosphate (Ins 1,3,4-P3). This latter molecule can be converted into inositol 1,4-bisphosphate, then into inositol 

1-phosphate and ultimately back into PIP2 (Fig. 6.9). Hence, the Ins 1,4,5-P3 that is released into the cytoplasm can be metabolised by two separate routes. 

More recently, the importance of a group of highly polar inositol lipids, present in neutrophils and many other cell types, has been recognised. Activation of neutrophils by fMet-Leu-Phe results in the transient accumulation of phosphatidylinositol 3-phosphate (Ptdlns 3-P), phosphatidylinositol 3,4-bisphosphate (Ptdlns 3,4-P2) and phosphatidylinositol 3,4,5-trisphosphate (Ptdlns 3,4,5-P3). Apparently, the enzyme phosphatidylinositol 3-hydroxy (3-OH) kinase plays a key role in the formation of these novel lipids. This enzyme can catalyse the formation of these lipids from phosphatidylinositol, phosphatidylinositol 4-phosphate (Ptdlns 4-P) and phosphatidylinositol 4,5 bisphosphate (Ptdlns 4,5-P2) in vitro (Fig. 6.10). Alternatively, it is possible that Ptdlns 3,4-P2 and Ptdlns 3-P are derived from the sequential dephosphorylation of Ptdlns 3,4,5-P3. 

The idea that stimulated inositide metabolism was involved in increases in cytoplasmic Ca2+ was first proposed by Bob Michell (1975). To date, over 20 different inositol phosphates can be isolated from stimulated cells, but so far only one of these molecules can be ascribed a definite function Ins 1,4,5-P3, which is released into the cytoplasm following PLC hydrolysis of PIP2, liberates Ca2+ from intracellular stores. A role for Ins 1,3,4,5-P4in opening a Ca2+ gate , thus allowing the influx of Ca2+ from the external 

Ptdlns 3-phosphate Ptdlns 3,4-bisphosphate Ptdlns 3,4,5-trisphosphate 

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