[Contemporary concepts in studies on cyclic AMP and its role in the inflammatory reaction]

Krzysztof Pociecha, Katarzyna Przejczowska-Pomierny, Agnieszka Cios, Elżbieta Wyska
Postȩpy Higieny i Medycyny Doświadczalnej 2015, 69: 777-98
Although cyclic AMP (cAMP) was discovered more than 50 years ago, new reports of unknown functions of this nucleotide still appear in the literature. It is synthesized from adenosine triphosphate in a reaction catalysed by adenylyl cyclase. In mammalian cells nine membrane-associated and one soluble adenylyl cyclase isoforms occur. Most of them interact with Gs- or Gi-protein coupled receptors. The only way of cAMP degradation is the reaction of hydrolysis catalyzed by phosphodiesterase. In humans there are 11 families of these enzymes, which differ in substrate affinity, structure, place of occurrence and mechanism of regulation. Modulation of activity of these enzymes is an important direction in the search for new drugs. The effectors of cAMP are: protein kinase A (PKA), Epac proteins, and cAMP-dependent ion channels. In the course of the inflammatory response, the increase in cAMP level may lead to an increase in IL-10 expression, inhibition of TNF-α, IL-12, and MIP-1β release, as well as to a reduction inthe permeability of blood vessels. In addition, cAMP regulates the process of phagocytosis. In the majority of cases, acting via PKA it induces cell apoptosis, and by activating Epac proteins it inhibits cell death. It has been shown that the levels of cAMP vary in different intracellular spaces due to the discretely positioned proteins responsible for its synthesis and breakdown. Moreover, the enzymatic pathway responsible for the extracellular degradation of cAMP has been discovered. Two transporters, ABCC4 and ABCC5, are involved in the transport of cAMP outside the cells. Administration of drugs modulating the level of this nucleotide to rodents leads to changes in its concentrations in blood and/or animal tissues. Progress in research on cAMP has become possible to a large extent due to the emergence of new analytical methods for the determination of its concentrations in biological material.

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