RETICULUMPI 4,5-bisphosphate [PI(4,5)P2] inositol 1,4,5-trisphosphate (IP3)
Figure 15–28 The hydrolysis of PI(4,5) P2 by phospholipase C-β. Two second messengers are produced directly from the hydrolysis of PI(4,5)P2: inositol 1,4,5-trisphosphate (IP3), which diffuses through the cytosol and releases Ca2+ from the endoplasmic reticulum, and diacylglycerol, which remains in the membrane and helps to activate protein kinase C (PKC; see Figure 15–29). There are several classes of phospholipase
C: these include the β class, which is activated by GPCRs; as we see later, the γ class is activated by a class of enzyme-coupled receptors called receptor tyrosine kinases (RTKs).
signal molecule PI 4,5-bisphosphate activated GPCR activated Gqprotein activated phospholipase C-˜diacylglycerol plasma membrane [PI(4,5)P2] activated protein kinase C Ca inositol 1,4,5-trisphosphate (IP3) lumen of endoplasmic reticulum open IP3-gated Ca2+-release channel 2+ GTPP P P P P P ˜°˛ in pain and inflammatory responses, for example, and many anti-inflammatory drugs (such as aspirin, ibuprofen, and cortisone) act in part by inhibiting their synthesis.
Ca2+ Functions as a Ubiquitous Intracellular Mediator
Many extracellular signals, and not just those that work via G proteins, trigger an increase in cytosolic Ca2+ concentration. In muscle cells, Ca2+ triggers contraction, and in many secretory cells, including nerve cells, it triggers secretion. Ca2+ has numerous other functions in a variety of cell types. Ca2+ is such an effective signaling mediator because its concentration in the cytosol is normally very low (~10–7 M), whereas its concentration in the extracellular fluid (~10–3 M) and in the lumen of the ER [and sarcoplasmic reticulum (SR) in muscle] is high. Thus, there is a large gradient tending to drive Ca2+ into the cytosol across both the plasma membrane and the ER or SR membrane. When a signal transiently opens Ca2+ channels in these membranes, Ca2+ rushes into the cytosol, and the resulting 10–20-fold increase in the local Ca2+ concentration activates Ca2+-responsive proteins in the cell.
Some stimuli, including membrane depolarization, membrane stretch, and certain extracellular signals, activate Ca2+ channels in the plasma membrane, resulting in Ca2+ influx from outside the cell. Other signals, including the GPCR-mediated signals described earlier, act primarily through IP3 receptors to stimulate Ca2+ release from intracellular stores in the ER (see Figure 15–29). The ER membrane also contains a second type of regulated Ca2+ channel called the ryanodine receptor (so called because it is sensitive to the plant alkaloid ryanodine), which opens in response to rising Ca2+ levels and thereby amplifies the Ca2+ signal, as we describe shortly.
Several mechanisms rapidly terminate the Ca2+ signal and are also responsible for keeping the concentration of Ca2+ in the cytosol low in resting cells. Most importantly, there are Ca2+-pumps in the plasma membrane and the ER membrane that use the energy of ATP hydrolysis to pump Ca2+ out of the cytosol. Cells such as muscle and nerve cells, which make extensive use of Ca2+ signaling, have an additional Ca2+ transporter (a Na+-driven Ca2+ exchanger) in their plasma membrane that couples the efflux of Ca2+ to the influx of Na+.