Action of cyclic AMP

Cells can t be turned on forever. Something must modulate the response. In fact, each step is reversible. Starting from the target proteins, a protein phosphatase hydrolyzes the phosphate from the proteins. Cyclic AMP is hydrolyzed by a phosphodiesterase. 

Perhaps a key point in the modulation system is GTP hydrolysis by the G-protein. This causes adenylate cyclase to return to the unstimulated state. 

All signaling mechanisms must have this modulation feature to allow the possibility of control. For example, the Ras protein of mammalian cells is a membrane-bound GTPase. Mutations that decrease Ras s GTPase activity can contribute to uncontrolled growth (i.e., tumor formation) of mammalian cells. 

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There is some evidence to suggest that these drugs may owe their activity to inhibition of the enzyme that is responsible for hydrolysis of 3, 5 -cyclic AMP (itself a guanine derivative) and thus prolong the action of cyclic AMP. 

Moffett, S. Rousseau, G. Lagace, M. Bouvier, M. The palmitoylation state of the 2-adrenergic receptor regulates the synergistic action of cyclic AMP-dependent protein kinase and )8-adrenergic receptor kinase involved in its phosphorylation and desensitization. J. Neurochem., 76, 269-279 (2001)... 

Lichtenstein, M. L., De Bernardo, R. The immediate allergie response In vitro action of cyclic AMP-active and other drugs on the two stages of histamine release. J. Immunol. 107, 1131 (1971)... 

P. Cohen and D.G. Hardie. 1991. The actions of cyclic AMP on biosynthetic processes are mediated indirectly by cyclic AMP-dependent protein kinases Biochim. Biophys. Acta 1094 292-299. (PubMed)... 

In animal cells, activation of protein kinase is the only well-understood action of cyclic AMP. The concentration of cyclic AMP needed for half-maximal stimulation of purified protein kinase from rabbit skeletal muscle was 15-30 nM [77]. The apparent K for ATP in the presence of 10 mM Mg was approximately 15 /xM. The binding of cyclic AMP to protein kinase was reversed by mild chemical treatment and by gel filtration on Sephadex [77]. 

An unexpected use for a tetracycline is in the treatment of chronic hyponatraemia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) when water restriction has failed. Demeclocycline produces a state of unresponsiveness to ADH, probably by inhibiting the formation and action of cyclic AMP in the renal tubule. It is effective and convenient to use in SIADH because this action is both dose-dependent and reversible. 

Several cyclic peptides have between two and eight cysteine residues. They adopt a triple-stranded 3-sheet structure e.g. vertebrate defensins) or a P-hairpin-like structure (e.g thanatin, androctonin, gomesin, and tachyplesin from arthropods and protegrin from vertebrate) or a mixed a-helix/p-sheet conformation (e.g. invertebrate and plant defensins, including some vertebrate defensins). Several reviews have been published in the past years discussing the structure and the mode of action of cyclic AMPs from animals. The reader is referred to the reviews written by Powers and Hancock [108], Bulet et al. [4], Ganz [8], and Yount [88]. In this chapter, only cyclic peptides with a P-hairpin-like structure will be discussed. 

Figure 8-3. The production and action of cyclic AMP (cAMP). G = G protein. G proteins function when GTP is bound 0 = free catalytic subunits l ] = regulatory subunits of protein kinase A ffi = stimulates.

Biological Actions of Cyclic AMP Analogs George I. Drummond, David L, Severson e, 215... 

Cortisol secretion by isolated adrenal pouches in hypoxed dogs was stimulated by cyclic AMP, vasopressin and ACTH O. However, epinephrine and norepinephrine, which stimulate formation of cyclic AMP in fat pads, dichloroisoproterenol, which inhibits adenyl cyclase, or dihydroergota-mine, an inhibitor of action of cyclic AMP in the liver, failed to have any effect. 

To illustrate how the active site binds a specific substrate and then promotes a chemical change in the bound substrate, we examine the action of cyclic AMP-dependent protein kinase, now generally referred to as protein kinase A (PKA). This enzyme and other protein kinases, which add a phosphate group to serine, threonine, or tyrosine residues in proteins, are critical for regulating the activity of many cellular proteins, often in response to external signals. Because the eukaryotic protein kinases belong to a common superfam-lly, the structure of the active site and mechanism of phosphorylation are very similar in all of them. Thus protein kinase A can serve as a general model for this important class of enzymes. 

A number of drugs inhibit the antidiuretic actions of vasopressin. Lithium is of particular importance because of its use in the treatment of manic-depressive disorders. Lithium-induced polyuria is usually reversible. Acutely, lithium appears to reduce V -receptor-mediated stimulation of adeny-lyl cyclase. Also, hthium increases plasma levels of parathyroid hormone, a partial antagonist to vasopressin. In most patients, the antibiotic demeclocycline attenuates the antidiuretic effects of vasopressin, probably owing to decreased accumulation and action of cyclic AMP. 

However, cyclic AMP and its derivative, dibutyryl cyclic AMP, do inactivate the carboxylase under in vivo conditions. Therefore, the action of cyclic AMP is apparently not at the step of the activation of the carboxylase kinase, but at some other step leading to such activation. It is not entirely clear why the carboxylases from tissues other than mammary glands are not responsive to the cyclic AMP-dependent protein kinase. However, this lack of a cyclic AMP-dependent protein kinase effect could be related to experimental conditions since the suitability of the carboxylase as a substrate for the kinase is drastically aflFected hy cellular metabolites (see Section V). Allred and Harris (3) reported that the cyclic AMP-dependent phosphorylation site or entity dissociates itself from the carboxylase as the enzyme is purified. Thus, the purified preparation does not contain the site whose phosphorylation is stimulated by cyclic AMP. Two recently purified protein kinases active toward the liver acetyl-CoA carboxylase are cyclic AMP independent (70, 105). The properties of these kinases will be discussed later. 

Although the concentrations of cyclic AMP required for the activation of cyclic AMP-dependent protein kinase have no effect on the phosphorylation and inactivation of the carboxylases from rat liver or epididymal fat tissues in vitro, high concentrations of cyclic AMP (0.1 mM and higher) can stimulate the phosphorylation of the carboxylase in the presence of low citrate concentrations (less than 2 mAf) (70). The exact relationship between citrate and the effect of cyclic AMP on phosphorylation is not fully understood. However, the stimulatory effect of cyclic AMP has proved to be very interesting. The high concentration of cyclic AMP (0.1 mM) required, and the lack of inhibition by the inhibitor proteins of cyclic AMP-dependent protein kinase in the action of cyclic AMP 65), suggested that the role of cyclic AMP for the stimulated phosphorylation of acetyl-CoA carboxylase in the rat liver system is different from its customary role of activation of protein kinase. This hypothesis has been proven to be true, as will be discussed below. 

Cyclic AMP Metabolism 530 Mode of Action of Cyclic AMP Calcium and Hormone Action 532 Conclusion 533... 

Drugs that interfere with the structure of microtubules such as colchicine or vinblastine inhibit the effects of ADH indicating that the integrity of the microtubules is necessary for the action of cyclic AMP [168]. 

The ineffectiveness of these related nucleotides in stimulatii progesterone synthesis serves to establish to a certain degree the specificity of the action of cyclic AMP on steroidogenesis in corpora lutea. 

On the basis of the above results it seems very likely that cyclic AMP acts as the mediator of the action of LH upon progesterone synthesis. Most of our current work has been directed toward determining how cyclic AMP mediates this effect. At this time our results are very preliminary and have been more informative in terms of indicatii what mechanisms are probably not correct among the current hypotheses than in indicating the correct mechanism of action of cyclic AMP. 

AMP levels. In this tissue it has also been possible to show that the lipolytic effects of the catecholamines can be mimicked by the direct application of cyclic AMP or its dibutyryl derivative which penetrates into the tissue more readily. The actions of cyclic AMP appear to be due to a direct activation of the enzyme triglyceride lipase, which controls the rate-limiting step in fat break-down. Here again the evidence is strongly in favour of the view that the -actions of the catecholamines are mediated through a stimulation of adenyl-cyclase activity. 

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