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FIGURE 13 Effects of cAMP. Activation of protein kinase A accounts for most of the cellular actions of cAMP (upper portion of the figure). Inactive protein kinase consists of two catalytic units (C), each of which is bound to a dimer of regulatory units (R). When two molecules of cyclic AMP bind to each regulatory unit, active catalytic subunits are released. Phosphorylation of enzymes, ion channels, and transcription factors of the CREB family activates or inactivates these proteins. Cyclic AMP also binds to the a subunits of cyclic nucleotide-gated ion channels (lower portion of the figure), causing them to open and allow influx of sodium and calcium.

CAMP,) COOH

FIGURE 13 Effects of cAMP. Activation of protein kinase A accounts for most of the cellular actions of cAMP (upper portion of the figure). Inactive protein kinase consists of two catalytic units (C), each of which is bound to a dimer of regulatory units (R). When two molecules of cyclic AMP bind to each regulatory unit, active catalytic subunits are released. Phosphorylation of enzymes, ion channels, and transcription factors of the CREB family activates or inactivates these proteins. Cyclic AMP also binds to the a subunits of cyclic nucleotide-gated ion channels (lower portion of the figure), causing them to open and allow influx of sodium and calcium.

activated proteins and return the cell to its unstimu-lated state.

Protein-kinase-A-dependent phosphorylation of enzymes leads to rapid responses, including mobilization of metabolic fuels, secretion, muscle contraction or relaxation, and changes in membrane permeability. Cyclic AMP can also signal changes in gene expression. Some activated PKA migrates to the nucleus, where it catalyzes the phosphorylation of certain transcription factors that regulate the expression of certain genes by binding to nucleotide sequences called response elements, in the promoter region. Because regulation of these genes is sensitive to cAMP, the regulatory sequence is called the cAMP response element (CRE), and the phosphoprotein that binds to it is called a cAMP response element binding (CREB) protein. One or more forms of CREB are found in the nuclei of most cells and control expression of genes that are involved in such diverse processes as learning, glucose synthesis, and ion excretion.

Some effects of cAMP are independent of PKA. Cyclic AMP can also bind directly to certain plasma membrane proteins that function as cation channels. These proteins form tetrameric structures that span the entire thickness of membrane. When bound to cAMP, they change their configuration in such a manner that they form an open channel that allows sodium and calcium ions to enter the cell. Activation of cAMP gated cation channels in olfactory receptor cells, for example, initiates the transmission of an electrical impulse in olfactory nerves. Cyclic AMP gated cation channels are widely distributed, but except for their role in sensory perception their function is not understood.

Calcium and Calmodulin

Although calcium is always abundantly available in extracellular fluid, it too can serve as a second messenger, largely because its concentration in cytoplasm can undergo abrupt dramatic changes. In the resting state, the intracellular free calcium concentration is about 10,000 times lower than that of the extracellular fluid. This enormous discrepancy is maintained by limited permeability of the plasma membrane to calcium, the presence of a large reservoir of intracellular proteins that can bind calcium and therefore buffer its concentration, and by membrane proteins that can transfer calcium out of the cell or sequester it in storage sites in the endoplasmic reticulum. The pumps and exchangers that carry out these tasks are discussed in Chapter 3. After stimulation by some agonists, the concentration of free calcium may increase tenfold or more. This dramatic change is brought about in part by release of calcium from within the endoplasmic reticu-lum, and in part by an influx of calcium from the extracellular fluid through channels that can be induced to open and allow calcium ions to diffuse across the membrane. Some calcium channels are voltage sensitive and open when the membrane depolarizes to some critical level (see Chapter 4). Opening of voltage-sensitive calcium channels requires the flow of current in the form of positively charged ions that cross the membrane through other ion-specific channels. Some calcium channels are controlled by phosphorylation-dephosphorylation reactions and some are even activated by calcium itself.

Increased calcium concentrations activate a variety of enzymes and trigger such events as muscular contraction, secretion, and polymerization of tubulin to form microtubules. Although calcium can directly activate some proteins, it generally does not act alone. Virtually all cells are endowed with a protein called calmodulin, which reversibly binds four calcium ions. When complexed with calcium, the configuration of calmodu-lin is modified in a way that enables it to bind to certain enzymes, usually protein kinases, and thereby activate them. Calcium/calmodulin-dependent protein kinase II (CAM-kinase II) is a widely distributed multifunctional protein kinase that may catalyze the phosphorylation of many of the same substrates as PKA, including CREB and other nuclear transcription factors. Several other proteins (e.g., troponin C) that are closely related to

calmodulin also bind calcium and activate enzymes in some cells (see Chapter 7). Increased cytosolic calcium can also activate calcium-dependent protein phospha-tases and proteases and thereby also modify the activities of some proteins. Free calcium is removed from the cytosol by proteins in the plasma membrane that transfer one molecule of calcium to the extracellular fluid in exchange for two molecules of sodium and by ATP-dependent membrane pumps that may resequester it in intracellular storage sites or transfer it to the extracellular fluid. As the intracellular concentration of free calcium is restored to its resting low level, calcium is released from calmodulin, which then dissociates from the various enzymes it has activated, and the resting state is reinstituted.

The DAG and IP3 System

Both products of phospholipase-C-catalyzed hydrolysis of phosphatidylinositol 4,5 bisphosphate, DAG, and IP3 behave as second messengers (Fig. 14). IP3 diffuses through the cytosol to reach its receptors in the membranes of the endoplasmic reticulum and stimulate release of stored calcium into the cytoplasm. Because of its lipid solubility, DAG remains associated with the plasma membrane, promotes the translocation of another protein kinase (protein kinase C, or PKC) from the cytosol to the plasma membrane by increasing its affinity for phosphatidylserine in the membrane, and activates it. Protein kinase C has also been called the

FIGURE 14 Signal transduction through the inositol trisphosphate (IP3) diacylglycerol (DAG) second messenger system. Phosphatidyli-nositol 4,5 bisphosphate (PIP2) is cleaved into IP3 and DAG by the action of a phospholipase C (PLC). DAG activates protein kinase C (PKC), which then phosphorylates a variety of proteins to produce various cell-specific effects. IP3 binds to its receptor in the membrane of the endoplasmic reticulum causing release of calcium (Ca2+) which further activates PKC, directly activates or inhibits enzymes or ion channels, or binds to calmodulin, which then binds to and activates protein kinases and other proteins.

FIGURE 14 Signal transduction through the inositol trisphosphate (IP3) diacylglycerol (DAG) second messenger system. Phosphatidyli-nositol 4,5 bisphosphate (PIP2) is cleaved into IP3 and DAG by the action of a phospholipase C (PLC). DAG activates protein kinase C (PKC), which then phosphorylates a variety of proteins to produce various cell-specific effects. IP3 binds to its receptor in the membrane of the endoplasmic reticulum causing release of calcium (Ca2+) which further activates PKC, directly activates or inhibits enzymes or ion channels, or binds to calmodulin, which then binds to and activates protein kinases and other proteins.

calcium, phospholipid-dependent protein kinase because the members of this enzyme family that were initially discovered require both phosphatidylserine and calcium to be fully activated. The simultaneous increase in cytosolic calcium concentration resulting from the action of IP3 complements DAG in stimulating the catalytic activity of some members of the PKC family. Some members of the PKC family are stimulated by DAG even when cytosolic calcium remains at resting levels. Proteins phosphorylated by the various forms of PKC are involved in regulation of metabolism, membrane permeability, muscle contraction, secretion, and gene expression.

Inositol 1,4,5 trisphosphate is cleared from cells by stepwise dephosphorylation to inositol. DAG is cleared by addition of a phosphate group to form phosphatidic acid, which may then be converted to a triglyceride or resynthesized into a phospholipid. Phosphatidylinosi-tides of the plasma membrane are regenerated by combining inositol with phosphatidic acid, which may then initiate stepwise phosphorylation of the inositol.

Arachidonic Acid Metabolites

The phosphatidylinositol precursor of IP3 and DAG also contains a 20-carbon polyunsaturated fatty acid called arachidonic acid (Fig. 15). This fatty acid is typically found in ester linkage with carbon 2 of the glycerol backbone of phospholipids and may be liberated by the action of a diacylglyceride lipase from the DAG formed in the breakdown of phosphatidylinositol. Liberation of arachidonic acid is the rate-determining step in the formation of the thromboxanes, the pros-taglandins, and the leukotrienes (see Chapter 40). These compounds, which are produced in virtually all cells, diffuse across the plasma membrane and behave as local regulators of nearby cells. Thus, the same ligand-receptor interaction that produces DAG and IP3 as second messengers to communicate with cellular organelles frequently also results in the formation of arachidonate derivatives that inform neighboring cells that a response has been initiated. Phosphatidylinositol is only one of several membrane phospholipids that contain arachidonate. Arachidonic acid is also released from more abundant membrane phospholipids by the actions of the phospholipase A2 class of enzymes that can be activated by calcium, by PKC-dependent phos-phorylation, and by fly subunits of G-proteins.

G-Protein-Coupled Receptors and Ion Channels

Evidence is accumulating that G-proteins also link activated receptors to ion channels, which act as the effectors of agonist stimulation in much the same manner that adenylyl cyclase or phospholipase C are

Phosphatidyl inositol-bis-phosphate

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