for example, cAMP activates the gene that encodes this hormone. The regulatory region of the somatostatin gene contains a short cis-regulatory sequence, called the cyclic AMP response element (CRE), which is also found in the regulatory region of many other genes activated by cAMP. A specific transcription regulator called CRE-binding (CREB) protein recognizes this sequence. When PKA is activated by cAMP, it phosphorylates CREB on a single serine; phosphorylated CREB then recruits a transcriptional coactivator called CREB-binding protein (CBP), which stimulates the transcription of the target genes (Figure 15–27). Thus, CREB can transform a short cAMP signal into a long-term change in a cell, a process that, in the brain, is thought to play an important part in some forms of learning and memory.
Many GPCRs exert their effects through G proteins that activate the plasma-membrane-bound enzyme phospholipase C-β (PLCβ). Table 15–2 lists some examples of responses activated in this way. The phospholipase acts on a phosphorylated inositol phospholipid (a phosphoinositide) called phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], which is present in small amounts in the inner half of the plasma membrane lipid bilayer (Figure 15–28). Receptors that activate this inositol phospholipid signaling pathway mainly do so via a G protein called Gq, which activates phospholipase C-β in much the same way that Gs activates adenylyl cyclase. The activated phospholipase then cleaves the PI(4,5)P2 to generate two products: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. At this step, the signaling pathway splits into two branches.
IP3 is a water-soluble molecule that leaves the plasma membrane and diffuses rapidly through the cytosol. When it reaches the endoplasmic reticulum (ER), it binds to and opens IP3-gated Ca2+-release channels (also called IP3 receptors) in the ER membrane. Ca2+ stored in the ER is released through the open channels, quickly raising the concentration of Ca2+ in the cytosol (Figure 15–29). The increase in cytosolic Ca2+ propagates the signal by influencing the activity of Ca2+sensitive intracellular proteins, as we describe shortly.
At the same time that the IP3 produced by the hydrolysis of PI(4,5)P2 is increasing the concentration of Ca2+ in the cytosol, the other cleavage product of the PI(4,5)P2, diacylglycerol, is exerting different effects. It also acts as a second messenger, but it remains embedded in the plasma membrane, where it has several potential signaling roles. One of its major functions is to activate a protein kinase called protein kinase C (PKC), so named because it is Ca2+-dependent. The initial rise in cytosolic Ca2+ induced by IP3 alters the PKC so that it translocates from the cytosol to the cytoplasmic face of the plasma membrane. There it is activated by the combination of Ca2+, diacylglycerol, and the negatively charged membrane phospholipid phosphatidylserine (see Figure 15–29). Once activated, PKC phosphorylates target proteins that vary depending on the cell type. The principles are the same as discussed earlier for PKA, although most of the target proteins are different.
Diacylglycerol can be further cleaved to release arachidonic acid, which can either act as a signal in its own right or be used in the synthesis of other small lipid signal molecules called eicosanoids. Most vertebrate cell types make eicosanoids, including prostaglandins, which have many biological activities. They participate