Phosphodiesterases cAMP hydrolyzed

Lead also has been shown to substitute for calcium in the activation of calmodulin, but this requires higher levels of lead than does the activation of protein kinase C. Nevertheless, the affinity of lead for calmodulin is higher than that of calcium. Once activated, calmodulin regulates the activity of certain enzymes and transporters. For example, it activates c-AMP phosphodiesterase to hydrolyze and terminate the action of cAMP, another second messenger (Bressler and Goldstein 1991 Goldstein 1993 Goering 1993). 

All the p-adrenergic receptors are coupled to adenylate cyclase via specific G stimulatory proteins (Gs). When agonist binds to the p-adrenergic receptors, the a-subunit migrates through the membrane and stimulates adenylate cyclase to form cyclic adenosine monophosphate (cAMP) from adenosine triphosphate. Once formed in the cell, cAMP activates protein kinase A, which catalyzes the phosphorylation of numerous proteins, thereby regulating their activity and leading to characteristic cellular responses. The intracellular enzyme phosphodiesterase (PDE) hydrolyzes cAMP to form AMP and terminates its action (Fig. 44.7). 

The cAMP formed by adenylyl cyclase (Figure 15.20) does not persist because 5 -phosphodiesterase activity prevalent in cells hydrolyzes cAMP to give 5 -AMP. Caffeine inhibits 5 -phosphodi-esterase activity. Describe the effects on glycogen phosphorylase activity that arise as a consequence of drinking lots of caffeinated coffee. 

Cyclic AMP (cAMP) (Figure 18-5) is formed from ATP by adenylyl cyclase at the inner surface of cell membranes and acts as an intracellular second messenger in response to hormones such as epinephrine, norepinephrine, and glucagon. cAMP is hydrolyzed by phosphodiesterase, so terminating hormone action. In hver, insulin increases the activity of phosphodiesterase. 

Activation of adenylyl cyclase by an activated G-protein coupled receptor results in the synthesis of cAMP. The cAMP activates a downstream kinase, protein kinase A. Phosphodiesterase hydrolyzes and inactivates the cAMP. 

Cyclic nucleotides (cAMP and cGMP) are hydrolyzed to destroy the signal. The enzyme that hydrolyzes them is called a phosphodiesterase (more formally, a cAMP or cGMP phosphodiesterase). The signal that activates the synthesis of the cyclic nucleotide will often inhibit the phosphodiesterase. 

FIGURE 21-2 Chemical pathways for the synthesis and degradation of cAMP. cAMP is synthesized from ATP by the enzyme adenylyl cyclase with the release of pyrophosphate, and is hydrolyzed into 5 -AMP by the enzyme phosphodiesterase. Both reactions require Mg2. Analogous reactions underlie the synthesis and degradation of cGMP (not shown). PP, inorganic pyrophosphate. 

Fig. 7.6. Feedback control of protein kinase A by a phosphodiesterase. On activation of protein kinase A, the catalytic C subnnits are released, which then phosphorylate a phosphodiesterase, in addition to other substrates. The phosphodiesterase is activated by the phosphorylation and hydrolyzes cAMP to AMP, whereby the signal transduction via protein kinase A is reduced or terminated.

The cAMP second messenger pathway. Key proteins include hormone receptors (Rec), a stimulatory G protein (Gs), catalytic adenylyl cyclase (AC), phosphodiesterases (PDE) that hydrolyze cAMP, cAMP-dependent kinases, with regulatory (R) and catalytic (C) subunits,... 

Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family (Figure 20-3). Because the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cyclic AMP (cAMP) and, in some tissues, cGMP. CAMP is responsible for a myriad of cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells. 

Hydrolysis of cAMP cAMP is rapidly hydrolyzed to 5-AMP by cAMP phosphodiesterase, one of a family of enzymes that cleave the cyclic 3 5 -phosphodiester bond. 5-AMP is not an intracellular signalling molecule. Thus, the effects of neurotransmitter- or hormone-mediated increases of cAMP are rapidly terminated if the extracellular signal is removed. [Note Phosphodiesterase is inhibited by methylxanthine derivatives, such as theophylline and caffeine.3]... 

In all cases the cells also utilize cAMP as an internal second messenger. For D. discoideum the components of the chemotactic-aggregation system include a 41-kDa cAMP receptor on the outside, adenylate cyclase, an extracellular diesterase that specifically hydrolyzes the cAMP to AMP, and a diesterase inhibitor protein.35 227-230 The inhibitor keeps the phosphodiesterase largely inactive initially, but when cAMP concentrations build up synthesis of the inhibitor is repressed and the cAMP is hydrolyzed, a necessary condition for retaining sensitivity of the receptors for the arriving pulses of cAMP. 

Each step requires activation of an enzyme, and each enzyme can perform the next step many times. This gives a cascade effect, in which each step is an amplification of the one preceding it. There are a number of ways in which the process can slow down or stop. The epinephrine can leave its receptor this would cause adenyl cyclase to assume its inactive or dormant conformation. The cAMP can be hydrolyzed to AMP this process is catalyzed by the enzyme phosphodiesterase. The concentration of ATP will increase (as the result of the degradation of glycogen and the production... 

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