The link between membrane binding of a ligand that acts via Ca2+ and the prompt increase in the cytoplasmic Ca2+ concentration is often IP3 . When one of these ligands binds to its receptor, activation of the receptor produces activation of phospholipase C (PLC) on the inner surface of the membrane. Ligands bound to GPCR can do this through the Gq heterotrimeric G-proteins, while ligands bound to tyro sine kinase receptors can do this through other cell signaling pathways. PLC has at least eight isoforms; PLCβ is activated by heterotrimeric G-proteins, while PLCγ forms are activated through tyrosine kinase receptors. PLC isoforms can catalyze the hydrolysis of the membrane lipid phosphatidylinositol 4,5-diphosphate (PIP2) to form IP3 and DAG (Figure 1). The IP3 diffuses to the endoplasmic reticulum where it triggers the release of Ca2+ into the cytoplasm by binding the IP3 receptor, a ligand-gated Ca2+ channel (Figure 2). DAG is also a second messenger; it stays in the cell membrane where it activates one of several isoforms of protein kinase C.
Fig1. Metabolism of phosphatidylinositol in cell membranes. Phosphatidylinositol is successively phosphorylated to form phosphatidylinositol 4-phosphate (PIP), then phosphatidylinositol 4,5-bisphosphate (PIP2 ). Phospholipase Cβ and phospholipase Cγ catalyze the breakdown of PIP2 to inositol 1,4,5-trisphosphate (IP3 ) and diacylglycerol. Other inositol phosphates and phosphatidylinositol derivatives can also be formed. IP3 is dephosphorylated to inositol, and diacylglycerol is metabolized to cytosine diphosphate (CDP)-diacylglycerol. CDP diacylglycerol and inositol then combine to form phosphatidylinositol, completing the cycle. (Modified with permission from Berridge MJ: Inositol triphosphate and diacylglycerol as second messengers, Biochem J 1984; June 1;220(2):345–360.)
Fig2. Diagrammatic representation of release of inositol trisphosphate (IP3 ) and diacylglycerol (DAG) as second messengers. Binding of ligand to G-protein–coupled receptor activates phospholipase C (PLC)β . Alternatively, activation of receptors with intracellular tyrosine kinase domains can activate PLCγ. The resulting hydrolysis of phosphatidylinositol 4,5-diphosphate (PIP2 ) produces IP3 , which releases Ca2+ from the endoplasmic reticulum (ER), and DAG, which activates protein kinase C (PKC). CaBP, Ca2+-binding proteins; ISF, interstitial fluid.
