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As discussed in Chapter 15, hormonal stimulation of some G protein–coupled receptors leads to the activation of phospholipase C (PLC). This membrane-associated enzyme then cleaves phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] to generate two important second messengers: 1,2-diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP₃). Signaling via the IP₃/DAG pathway leads to an increase in cytosolic Ca²⁺ and to activation of protein kinase C (see Figure 15-34).

Although we did not mention it during our discussion of phospholipase C in Chapter 15, it is specifically the β isoform of this enzyme (PLC_β) that is activated by GPCRs. Many RTKs and cytokine receptors can also initiate the IP₃/DAG pathway by activating another isoform of phospholipase C, the γ isoform (PLC_γ), which contains SH2 domains and is localized to the cytosol. The SH2 domains of PLC_γ bind to specific phosphotyrosines on the activated receptors, thus positioning the enzyme close to its substrate, PI(4,5)P₂, on the cytosolic face of the plasma membrane. In addition, the kinase activity associated with receptor activation phosphorylates tyrosine residues on the bound PLC_γ, enhancing its hydrolase activity. Thus activated RTKs and cytokine receptors promote PLC_γ activity in two ways: by localizing the enzyme to the membrane and by phosphorylating it. As seen in Chapter 15, the IP₃/DAG pathway initiated by PLC has multiple physiological effects.