Cyclic AMP inhibition

Smolen, J. E., Stoehr, S. J., Kuczynski, B. (1991). Cyclic AMP inhibits secretion from electroporated human neutrophils. J. Leuk. Biol. 49, 172-9. 

Hayashi, S., R. Morishita, H. Matsushita, H. Nakagami, Y. Taniyama, T. Nakamura, M. Aoki, K. Yamamoto, J. Higaki, and T. Ogihara. 2000. Cyclic AMP inhibited proliferation of human aortic vascular smooth muscle cells, accompanied by induction of p53 and p21. Hypertension 35 237-243. 

Prostacyclin (PGI2). Released by endothelium. Activates platelet Gs proteiu-liuked receptors, which in turn activate adenyl cyclase increased levels of cyclic AMP inhibit platelet... 

In most cases, the effect of cyclic AMP has been to increase the activity of protein kinase, but instances have been found in which the cyclic nucleotide decreased the protein kinase activity. In these cases the level of substrate phosphorylation was lower in the presence than in the absence of cyclic AMP. Such a net decrease in the level of phosphorylation of a protein substrate may result either from a decrease in the activity of a protein kinase or from an increase in the activity of a protein phosphatase, or both [81]. Cyclic AMP-inhibited protein kinases have been described [82]. 

It is known that cyclic AMP inhibits the release of a chemical mediator firm the mast cell. So when cyclic AMP phosphodiesterase is inhibited by some inhibitor the concentration of cyclic AMP is increased to inhibit the release of die chemical mediator from the mast cell. Inhibitors against cyclic AMP phosphodiesterase may be useful in the therapy for allergic diseases. In addition, by the presence of 5-lipoxygenase, free arachidonic acid is converted to leukotrienes, which is one of the chemical mediators known as a slow reacting substance of anaphylaxis. Therefore, specific inhibitors of 5-lipoxygenase may be useful in the therapy for allergic diseases. 

There is no evidence that cyclic AMP interferes with the antigen-antibody reaction and so it is plausible that cyclic AMP inhibits histamine secretion either by blocking directly the calcium channels or by interfering with the coupling between the... 

In 1973 when Carlson and Kim reported that acetyl-CoA carboxylase was regulated by a covalent modification mechanism involving interconversion between the phosphorylated (inactive) and the dephos-phorylated form (active) 19), there was some suggestive evidence for such a mechanism in the literature. For example, several investigators had observed that cyclic AMP and dibutyryl cyclic AMP inhibit the incorporation of [ Clacetate or [ CJglucose into fatty acid (5,12, 44, 45). Also treatment of rat or chicken liver and rat epididymal fat tissues in vitro with cyclic nucleotides results in the inactivation of acetyl-CoA carboxylase 4, 69). In addition to these observations, Greenspan and Lowenstein reported that crude enzsrme preparations of rat liver acetyl-CoA carboxylase were inactivated in the presence of ATP and Mg + and the inactivation was reversed by incubation with Mg + 34). However, ATP- and Mg -mediated inactivation was often explained in terms of a hypothetical, unstable E Biotin CO2 species 25, 39, 64). Thus, considerable controversy persisted for many years as to the occurrence of the covalent modification mechanism until several investigators published supportive evidence for this mechanism in various tissues 3, 16, 19, 41, 42, 66, 68, 105, 129). 

Fig. 11. Dose—response curves for (A,A) inhibition of cyclic AMP formation and stimulation of IP formation by carbachol (A,D) before and (A,H) after reduction of receptor number by irreversible alkylation (carbachol) is in M. Error bars ( ) are shown for some studies.

Depletion of ATP in the cells prevents maintenance of the membrane potential, inhibits the functioning of ion pumps, and attenuates cellular signal transduction (e.g., formation of second messengers such as inositol phos phates or cyclic AMP). A marked ATP depletion ultimately impairs the activ-itv of the cell and leads to ceil death. 

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. 

FIGURE 2.6 Production of cyclic AMP from ATP by the enzyme adenylate cyclase. Cyclic AMP is a ubiquitous second messenger in cells activating numerous cellular pathways. The adenylate cyclase is activated by the a subunit of Gs-protein and inhibited by the a-subunit of Gj-protein. Cyclic AMP is degraded by phosphodiesterases in the cell. 

Imidazo[l,2-c/][l,2,4]triazines 488 were prepared (78USP4096257) from the reaction of 2-imidazocarboxylic acid hydrazide 487 with orthoesters. They inhibited cyclic-AMP phosphodiesterase in the mouse skin phosphodiesterase test and had antiasthina. 

The steroid hormone 1,25-dihydroxy vitamin D3 (calcitriol) slowly increases both intestinal calcium absorption and bone resorption, and is also stimulated through low calcium levels. In contrast, calcitonin rapidly inhibits osteoclast activity and thus decreases serum calcium levels. Calcitonin is secreted by the clear cells of the thyroid and inhibits osteoclast activity by increasing the intracellular cyclic AMP content via binding to a specific cell surface receptor, thus causing a contraction of the resorbing cell membrane. The biological relevance of calcitonin in human calcium homeostasis is not well established. 

Interactions with caffeine and aspirin can increase the effects of ephedrine. Norepinephrine works in part by increasing the levels of cyclic aminomethyl propanol (AMP) in cells. Caffeine inhibits the enzyme that breaks down cyclic AMP. Together, ephedrine makes more cyclic AMP, and caffeine prevents it from breaking down. Aspirin inhibits the receptors that turn off release of norepinephrine. 

Figure 6. A hypothetical scheme for the control of the number of active crossbridges in smooth muscle. Following the activation of a smooth muscle by an agonist, the concentrations of intermediates along the main route begins to build up transiently. This is shown by the thickened arrows. Also, cAMP is generated which is universally an inhibitor in smooth muscle. Cyclic AMP in turn combines with protein kinase A, which accounts for most of its action. The downstream mechanisms, however, are not well worked out and at least three possibilities are likely in different circumstances. First, protein kinase A is known to catalyze the phosphorylation of MLCK, once phosphorylated MLCK has a relatively lower affinity for Ca-calmodulin so that for a given concentration of Ca-calmodulin, the activation downstream is reduced. The law of mass action predicts that this inhibition should be reversed at high calcium concentrations. Other cAMP inhibitory mechanisms for which there is evidence include interference with the SR Ca storage system, and activation of a MLC phosphatase.

Yang L, Jackson E, Woerner BM, Perry A, Piwnica-Worms D, Rubin JB (2007) Blocking CXCR4-mediated cyclic AMP suppression inhibits brain tumor growth in vivo. Cancer Res... 

The M2 and M4 receptors also show struetural similarities. Through G-protein (Gi) they inhibit cyclic AMP production and open K+ ehannels while activation of another G-protein (Go) closes Ca + channels. The latter effeet will cause membrane hyperpolarisation as will the Gpinduced inerease in K+ efflux. The reduction in cAMP production, although possibly leading to depolarisation, is more likely to explain the presynaptie reduction in ACh release assoeiated with the M2 receptor. 

In view of the known cellular actions of DA, such as increased K+ efflux and reduced Ca + currents associated with Dj receptor activation in cell lines, inhibition would be the expected response to DA, especially as cyclic AMP, which is increased by Dj receptor activation also inhibits striatal neurons. In fact although many DA synaptic effects are blocked by Dj antagonists like haloperidol, the role of Di receptors should not be overlooked. 

M Gilmour Buck, JA Zadunaisky. (1975). Stimulation of ion transport by ascorbic acid through inhibition of 3, 5 -cyclic AMP phosphodiesterase in the corneal epithehum and other tissue. Biochim Biophys Acta 376 82-88. 

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