Thus, the action of IP 3 is to produce yet another second messenger (perhaps a third messenger, in this case!) that triggers a whole spectrum of reactions in the cytosol. IP 3 binds to IP 3 receptors, channels that release calcium from the endoplasmic reticulum. The other messenger is inositol trisphosphate (IP 3), a molecule that leaves the cell membrane and diffuses within the cytosol. One of these messengers is diacylglycerol (DAG), a molecule that remains within the membrane and activates protein kinase C, which phosphorylates substrate proteins in both the plasma membrane and elsewhere. Phospholipase C splits the PIP 2 into two smaller molecules that each act as second messengers. This lipid component is cleaved by phospholipase C, an enzyme activated by certain G-proteins and by calcium ions. The two most important messengers of this type are produced from phosphatidylinositol bisphosphate (PIP 2). Remarkably, membrane lipids can also be converted into intracellular second messengers ( Figure 8.7D). Cyclic nucleotide signals are degraded by phosphodiesterases, enzymes that cleave phosphodiester bonds and convert cAMP into AMP or cGMP into GMP.ĭiacylglycerol and IP 3. These cyclic-nucleotide gated channels are ligand-gated (see Chapter 4) they are particularly important in phototransduction and other sensory transduction processes, such as olfaction. In addition, cAMP and cGMP can bind to certain ion channels, thereby influencing neuronal signaling. These enzymes mediate many physiological responses by phosphorylating target proteins, as described in the following section. The most common targets of cyclic nucleotide action are protein kinases, either the cAMP-dependent protein kinase (PKA) or the cGMP-dependent protein kinase (PKG). Once the intracellular concentration of cAMP or cGMP is elevated, these nucleotides can bind to two different classes of targets. Cyclic GMP is similarly produced from GTP by the action of guanylyl cyclase. This enzyme converts ATP into cAMP by removing two phosphate groups from the ATP. Cyclic AMP is produced when G-proteins activate adenylyl cyclase in the plasma membrane. Cyclic AMP is a derivative of the common cellular energy storage molecule, ATP. Another important group of second messengers are the cyclic nucleotides, specifically cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) ( Figure 8.7C). Among the biological signals that activate ryanodine receptors are cytoplasmic Ca 2+ and, at least in muscle cells, depolarization of the plasma membrane.Ĭyclic nucleotides. A second type of intracellular Ca 2+-releasing channel is the ryanodine receptor, named after a drug that binds to and partially opens these receptors. As the name implies, these channels are regulated by IP 3, a second messenger described in more detail below. One such channel is the inositol trisphosphate ( IP 3) receptor. These intracellular Ca 2+-releasing channels are gated, so they can be opened or closed in response to various intracellular signals. In addition, other channels allow Ca 2+ to be released from the interior of the endoplasmic reticulum into the cytosol. These can be voltage-gated Ca 2+ channels or ligand-gated channels in the plasma membrane, both of which allow Ca 2+ to flow down the Ca 2+ gradient and into the cell from the extracellular medium. The Ca 2+ ions that act as intracellular signals enter cytosol by means of one or more types of Ca 2+-permeable ion channels (see Chapter 4). Such buffers reversibly bind Ca 2+ and thus blunt the magnitude and kinetics of Ca 2+ signals within neurons. Finally, nerve cells contain other Ca 2+-binding proteins-such as calbindin-that serve as Ca 2+ buffers. These organelles can thus serve as storage depots of Ca 2+ ions that are later released to participate in signaling events. In addition to these plasma membrane mechanisms, Ca 2+ is also pumped into the endoplasmic reticulum and mitochondria. Most important in this maintenance are two proteins that translocate Ca 2+ from the cytosol to the extracellular medium: an ATPase called the calcium pump, and an Na + /Ca 2+ exchanger, which is a protein that replaces intracellular Ca 2+ with extracellular sodium ions (see Chapter 4). This steep Ca 2+ gradient is maintained by a number of mechanisms ( Figure 8.7B). The concentration of Ca 2+ ions outside neurons-in the bloodstream or cerebrospinal fluid, for instance-is several orders of magnitude higher, typically several millimolar (10 –3 M). Ordinarily the concentration of Ca 2+ ions in the cytosol is extremely low, typically 50–100 nanomolar (10 –9 M).
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