| Phosphatidylinositol 4,5-bisphosphate (PIP2)
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| Hydrolysis of a membrane phospholipid phosphatidylinositol 4,5-bisphosphate generates two second messengers
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| Figure 38.7 Structure and function of calmodulin. Binding of calcium induces a conformational change, allowing calmodulin to bind to and modify the activity of target signaling enzymes. |
| The major breakthrough in the search for the second messenger responsible for calcium mobilization came in the early 1980s, when it was found that stimulation of receptors that were known to increase the intracellular free Ca2+ concentration could activate the prior phospholipase C (PLC)-mediated hydrolysis of a minor phospholipid species, phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2, which typically represents about 0.4% of total phospholipids in membranes,
is generated from phosphatidylinositol by two kinases, phosphatidylinositol-4-kinase (PI-4-K or PI kinase) and phosphatidylinositol-5-kinase (PI-5-K or PIP kinase), both of which are found in the plasma membrane (Fig. 38.8A). PIP2 is hydrolyzed (Fig. 38.8B) by a PIP2-specific PLC, to generate two-second messengers: inositol trisphosphate (I-1,4,5-P3 or IP3) and diacylglycerol (DAG). IP3 is a water-soluble product, which is released into the cytosol and has been shown to mobilize intracellular stores of calcium. DAG is a lipid second messenger, which is anchored in the plasma membrane by virtue of its hydrophobic fatty-acid side chains and activates a key family of signaling enzymes known as protein kinase C (PKC) (Fig. 38.8B).
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