INVOLVEMENT OF INOSITOL LIPIDS AND THEIR PRODUCTS OF HYDROLYSIS IN CELLULAR SIGNALING

Ins(1,4,5) P-3 is a well-known inositol lipid-derived intracellular se cond messenger mobilizing intracellular calcium from internal stores. It is generated through two major signaling pathways: the former invol ves, G proteins-coupled receptors and the latter tyrosine kinase-linke d receptors. Ins(1,4,5) P-3 mobilizes intracellular calcium by binding to its receptor, showing structural and physiological similarities wi th the ryanodine receptor(another intracellular calcium channel). It i s metabolized by both an ins(1,4,5) P-3 5-phosphatase and 3-kinase rea ction. Biochemical and molecular studies indicated at each step of the signal transduction pathway extensive molecular heterogeneity in the synthesis and degradation of Inositol lipids derived molecules. Ins(1, 4,5) P-3 3-kinase consists in a family of calmodulin sensitive isoenzy mes producing Ins(1,3,4,5) P-4 (three isozymes). Ins(1,4,5) P-3 5-phos phatase dephosphorylates both Ins(1,4,5) P-3 and Ins(1,3,4,5) P-4. It is interesting to note that the Lowe's oculocerebrorenal syndrome may be caused by a defect in a gene that encodes an enzyme that metabolize s Ins(1,4,5) P-3, since type III of Ins(1,4,5) P-3 5-phosphatase shows high levels of sequence homology with the protein encoded by the Lowe 's syndrome deficient gene. PtdIns(4,5) P-2 is the phospholipase C sub strate to generate Ins(1,4,5) P-3 and diacylglycerol (DAG) but also th e substrate of a specific 3-kinase to produce PtdIns(3,4,5) P-3, anoth er potential second messenger. Like phospholipase C, PtdIns(4,5) P-2 3 -kinase may be activated through G protein-coupled receptors or tyrosi ne kinase-linked receptors. The levels of Ins(3,4,5,6) P-4 may also be regulated through the activation of receptors by extracellular signal s and this molecule may also play a role of second messenger.