Neurons use many different second messengers as intracellular signals. These messengers differ in the mechanism by which they are produced and removed, as well as their downstream targets and effects (Figure 8.7A). This section summarizes the attributes of some of the principal second messengers.

Figure 8.7

Neuronal second messengers. (A) Mechanisms responsible for producing and removing second messengers, as well as the downstream targets of these messengers. (B) Proteins involved in delivering calcium to the cytoplasm and in removing calcium from the cytoplasm. (more...)

• Calcium. The calcium ion (Ca²⁺) is perhaps the most common intracellular messenger in neurons. Indeed, few neuronal functions are immune to the influence—direct or indirect—of Ca²⁺. In all cases, information is transmitted by a transient rise in the cytoplasmic calcium concentration, which allows Ca²⁺ to bind to a large number of Ca²⁺-binding proteins that serve as molecular targets. One of the most thoroughly studied targets of Ca²⁺ is calmodulin, a Ca²⁺-binding protein abundant in the cytosol of all cells. Binding of Ca²⁺ to calmodulin activates this protein, which then initiates its effects by binding to still other downstream targets, such as protein kinases.
  Ordinarily the concentration of Ca²⁺ ions in the cytosol is extremely low, typically 50–100 nanomolar (10^–9 M). The concentration of Ca²⁺ ions outside neurons—in the bloodstream or cerebrospinal fluid, for instance—is several orders of magnitude higher, typically several millimolar (10^–3M). This steep Ca²⁺ gradient is maintained by a number of mechanisms (Figure 8.7B). Most important in this maintenance are two proteins that translocate Ca²⁺ from the cytosol to the extracellular medium: an ATPase called the calcium pump, and an Na⁺/Ca²⁺ exchanger, which is a protein that replaces intracellular Ca²⁺ with extracellular sodium ions (see Chapter 4). In addition to these plasma membrane mechanisms, Ca²⁺ is also pumped into the endoplasmic reticulum and mitochondria. These organelles can thus serve as storage depots of Ca²⁺ ions that are later released to participate in signaling events. Finally, nerve cells contain other Ca²⁺-binding proteins—such as calbindin—that serve as Ca²⁺ buffers. Such buffers reversibly bind Ca²⁺ and thus blunt the magnitude and kinetics of Ca²⁺ signals within neurons.
  The Ca²⁺ ions that act as intracellular signals enter cytosol by means of one or more types of Ca²⁺-permeable ion channels (see Chapter 4). These can be voltage-gated Ca²⁺ channels or ligand-gated channels in the plasma membrane, both of which allow Ca²⁺ to flow down the Ca²⁺ gradient and into the cell from the extracellular medium. In addition, other channels allow Ca²⁺ to be released from the interior of the endoplasmic reticulum into the cytosol. These intracellular Ca²⁺-releasing channels are gated, so they can be opened or closed in response to various intracellular signals. One such channel is the inositol trisphosphate (IP₃) receptor. As the name implies, these channels are regulated by IP₃, a second messenger described in more detail below. A second type of intracellular Ca²⁺-releasing channel is the ryanodine receptor, named after a drug that binds to and partially opens these receptors. Among the biological signals that activate ryanodine receptors are cytoplasmic Ca²⁺ and, at least in muscle cells, depolarization of the plasma membrane.
  These various mechanisms for elevating and removing Ca²⁺ ions allows precise control of both the timing and location of Ca²⁺ signaling within neurons, which in turn allows Ca²⁺ to control many different signaling events. For example, voltage-gated Ca²⁺ channels allow Ca²⁺ concentrations to rise very rapidly and locally within presynaptic terminals to trigger neurotransmitter release, as already described in Chapters 5 and 6. Slower and more widespread rises in Ca²⁺ concentration regulate a wide variety of other responses, including gene expression in the cell nucleus.
• Cyclic nucleotides. Another important group of second messengers are the cyclic nucleotides, specifically cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (Figure 8.7C). Cyclic AMP is a derivative of the common cellular energy storage molecule, ATP. Cyclic AMP is produced when G-proteins activate adenylyl cyclase in the plasma membrane. This enzyme converts ATP into cAMP by removing two phosphate groups from the ATP. Cyclic GMP is similarly produced from GTP by the action of guanylyl cyclase. Once the intracellular concentration of cAMP or cGMP is elevated, these nucleotides can bind to two different classes of targets. 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). These enzymes mediate many physiological responses by phosphorylating target proteins, as described in the following section. In addition, cAMP and cGMP can bind to certain ion channels, thereby influencing neuronal signaling. 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. Cyclic nucleotide signals are degraded by phosphodiesterases, enzymes that cleave phosphodiester bonds and convert cAMP into AMP or cGMP into GMP.
• Diacylglycerol and IP₃. Remarkably, membrane lipids can also be converted into intracellular second messengers (Figure 8.7D). The two most important messengers of this type are produced from phosphatidylinositol bisphosphate (PIP₂). This lipid component is cleaved by phospholipase C, an enzyme activated by certain G-proteins and by calcium ions. Phospholipase C splits the PIP₂ into two smaller molecules that each act as second messengers. 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. The other messenger is inositol trisphosphate (IP₃), a molecule that leaves the cell membrane and diffuses within the cytosol. IP₃ binds to IP₃ receptors, channels that release calcium from the endoplasmic reticulum. Thus, the action of IP₃ is to produce yet another second messenger (perhaps a third messenger, in this case!) that triggers a whole spectrum of reactions in the cytosol. The actions of DAG and IP₃ are terminated by enzymes that convert these two molecules into inert forms that can be recycled to produce new molecules of PIP₂.
• Nitric oxide. An unusual, but especially interesting, second messenger is nitric oxide (NO; Figure 8.7E). NO is produced by the action of nitric oxide synthase, an enzyme that converts the amino acid arginine into a metabolite, citrulline, and simultaneously generates NO. The nitric oxide synthase found in neurons is regulated by calcium binding to calmodulin and is coupled to a variety of neurotransmitter systems. In comparison to other second messengers used by neurons, NO is unusual in that it is a gas. NO also permeates the plasma membrane, meaning that NO generated within one cell can travel through the extracellular medium and act within other nearby cells. Thus, NO has a range of influence that extends well beyond the cell of origin. This property of NO makes it a useful signal for coordinating the activities of multiple cells in a very localized region; indeed, NO often is considered a neurotransmitter rather than a second messenger and may provide certain forms of synaptic plasticity in small networks of neurons (NO can diffuse only a few tens of micrometers from its site of production before it decays). At least some of the biological actions of NO are due to the activation of guanylyl cyclase, which then produces cGMP in target cells. NO reacts nonspecifically with many other molecules and decays spontaneously by reacting with oxygen to produce inactive nitrogen oxides. As a result, NO signals last for only a short time, on the order of seconds or less. NO may also be involved in some neurological diseases; for example, an emerging hypothesis is that an imbalance between nitric oxide and superoxide generation underlies some neurodegenerative diseases.