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 IP3 Pathway

The primary function of IP3 (D-myo-inositol-1,4,5-trisphosphate) is the release of calcium from the endoplasmic reticulum (ER) via the IP3-receptor (IP3R). The release of calcium from the ER is an important signaling event in all cells, but it must be regulated within the context of specific cell needs. Cytosolic calcium (Ca²⁺) binds to calmodulin, calcineurin and many other Ca²⁺-binding proteins to mediate a wide range of signaling events. IP3 is formed along with sn-diacylglycerol (DAG) through cleavage of phosphatidylinositol 4,5 bisphosphate (PIP2) by members of the PI-phospholipase C family of enzymes. To date, fourteen phosphatidylinositol-lipase C (PI-PLC) isozymes have been identified and classified into six families: the PLCbeta isoforms; PLCbeta1 (PI-PLC), PLCbeta2, PLCbeta3 and PLCbeta4; the PLCdelta isoforms; PLCdelta1, PLCdelta3 and PLCdelta4; PLCgamma isoforms, PLCgamma1 and PLCgamma2; PLCzeta and the PLCeta isoforms; PLCeta1 and PLCeta2. The PLC enzymes all share the ability to cleave PIP2 and form IP3. However, each is uniquely activated and inactivated by specific combinations of stimuli. These isozymes provide diversity of signaling and fine regulatory control of PIP2 lysis across the range of cell types and intracellular locations.

Phospholipase C enzymes are differentially activated directly and indirectly by a wide variety of cell surface receptors including growth factors, cytokines, GPCRs and integrins. The common element in all PLC activations involves the activation of kinases that phosphorylate the PLCs. These kinases include: mitogen receptor tyrosine kinases (RTK) such as PDGF, EGF, or FGF receptors; cytosolic Src-family kinases such as p72syk (B-cell antigen-receptor associated); TCR-associated tyrosine kinases; Emt/Itk/Tsk and p56lck) (Lck); and kinase activities mediated by GPCR trimeric G-proteins subunits, Galpha(q), Galpha11and Galpha12/13 and a variety of RAS family G-proteins.