The IP3 receptors and ryanodine receptors of the ER membrane have an important feature: they are both stimulated by low to moderate cytoplasmic Ca2+ concentrations. This Ca2+-induced calcium release (CICR) results in positive feedback,
Figure 15–29 How GPCRs increase cytosolic Ca2+ and activate protein kinase C. The activated GPCR stimulates the plasma-membrane-bound phospholipase C-β (PLCβ) via a G protein called Gq. The α subunit and βγ complex of Gq are both involved in this activation. Two second messengers are produced when PI(4,5)P2 is hydrolyzed by activated PLCβ. Inositol 1,4,5-trisphosphate (IP3) diffuses through the cytosol and releases Ca2+ from the ER by binding to and opening IP3-gated Ca2+-release channels (IP3 receptors) in the ER membrane. The large electrochemical gradient for Ca2+ across this membrane causes Ca2+ to escape into the cytosol when the release channels are opened. Diacylglycerol remains in the plasma membrane and, together with phosphatidylserine (not shown) and Ca2+, helps to activate protein kinase C (PKC), which is recruited from the cytosol to the cytosolic face of the plasma membrane. Of the 10 or more distinct isoforms of PKC in humans, at least 4 are activated by diacylglycerol (Movie 15.3).
which has a major impact on the properties of the Ca2+ signal. The importance of this feedback is seen clearly in studies with Ca2+-sensitive fluorescent indicators, such as aequorin or fura-2 (discussed in Chapter 9), which allow researchers to monitor cytosolic Ca2+ in individual cells under a microscope (Figure 15–30 and Movie 15.4).
When cells carrying a Ca2+ indicator are treated with a small amount of an extracellular signal molecule that stimulates IP3 production, tiny bursts of Ca2+ are seen in one or more discrete regions of the cell. These Ca2+ puffs or sparks reflect the local opening of small groups of IP3-gated Ca2+-release channels in the ER. Because various Ca2+-binding proteins act as Ca2+ buffers and restrict the diffusion of Ca2+, the signal often remains localized to the site where the Ca2+ enters the cytosol. If the extracellular signal is sufficiently strong and persistent, however, the local Ca2+ concentration can reach a sufficient level to activate nearby IP3 receptors and ryanodine receptors, resulting in a regenerative wave of Ca2+ release that moves through the cytosol (Figure 15–31), much like an action potential in an axon.
Figure 15–30 The fertilization of an egg by a sperm triggers a wave of cytosolic Ca2+. This starfish egg was injected with a Ca2+-sensitive fluorescent dye before it was fertilized. A wave of cytosolic Ca2+ (red), released from the ER, sweeps across the egg from the site of sperm entry (arrow). This Ca2+ wave changes the egg cell surface, preventing the entry of other sperm, and it also initiates embryonic development (Movie 15.5). The initial increase in Ca2+ is thought to be caused by a sperm-specific form of PLC (PLCζ) that the sperm brings into the egg cytoplasm when it fuses with the egg; the PLCζ cleaves PI(4,5)P2 to produce IP3, which releases Ca2+ from the egg ER. The released Ca2+ stimulates further Ca2+ release from the ER, producing the spreading wave, as we explain in Figure 15–31. (Courtesy of Stephen A. Stricker.)