200 ISSN 0026-8933, Molecular Biology, 2016, Vol. 50, No. 2, pp. 200–212. © Pleiades Publishing, Inc., 2016. Original Russian Text © K.V. Sivak, A.V. Vasin, V.V. Egorov, V.B. Tsevtkov, N.N. Kuzmich, V.A. Savina, O.I. Kiselev, 2016, published in Molekulyarnaya Biologiya, 2016, Vol. 50, No. 2, pp. 231–245. Adenosine A 2A Receptor as a Drug Target for Treatment of Sepsis K. V. Sivak a, *, A. V. Vasin a,b , V. V. Egorov a , V. B. Tsevtkov a , N. N. Kuzmich a , V. A. Savina a , and O. I. Kiselev a a Research Institute of Influenza, Ministry of Health of the Russian Federation, St. Petersburg, 197376 Russia b St. Petersburg State Polytechnical University, St. Petersburg, 195251 Russia *e-mail: konstantin.sivak@influenza.spb.ru Received August 16, 2015; in final form, October 26, 2015 Abstract—Sepsis is a generalized infection accompanied by response of the body that manifests in a clinical and laboratory syndrome, namely, in the systemic inflammatory response syndrome (SIRS) from the organ- ism to the infection. Although sepsis is a widespread and life-threatening disease, the assortment of drugs for its treatment is mostly limited by antibiotics. Therefore, the search for new cellular targets for drug therapy of sepsis is an urgent task of modern medicine and pharmacology. One of the most promising targets is the ade- nosine A 2A receptor (A 2A AR). The activation of this receptor, which is mediated by extracellular adenosine, manifests in almost all types of immune cells (lymphocytes, monocytes, macrophages, and dendritic cells) and results in reducing the severity of inflammation and reperfusion injury in various tissues. The activation of adenosine A 2A receptor inhibits the proliferation of T cells and production of proinflammatory cytokines, which contributes to the activation of the synthesis of anti-inflammatory cytokines, thereby suppressing the systemic response. For this reason, various selective A 2A AR agonists and antagonists may be considered to be drug candidates for sepsis pharmacotherapy. Nevertheless, they remain only efficient ligands and objects of pre-clinical and clinical trials. This review examines the molecular mechanisms of inflammatory response in sepsis and the structure and functions of A 2A AR and its role in the pathogenesis of sepsis, as well as examples of using agonists and antagonists of this receptor for the treatment of SIRS and sepsis. Keywords: sepsis, systemic inflammatory response syndrome, adenosine, adenosine A 2A receptors, agonists and antagonists of adenosine receptors DOI: 10.1134/S0026893316020230 Adenosine is an endogenous ligand of adenosiner- gic receptor system in mammals, it plays an important physiological regulatory role by modulating the activ- ity of various types of cells (platelet neurons, immune cells, smooth muscle bronchial, and vascular cells) [1]. Adenosine can be transported from cell or formed during extracellular hydrolysis of adenine nucleotides. In this case, ATP located in the extracellular space via ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39) is transformed to AMP, which is hydrolyzed to adenosine under the influence of ecto- 5'-nucleotidase (NT5E or CD73) [1, 2]. The bidirec- tional transport of adenosine through the cell mem- brane is mediated by equilibrative nucleoside trans- porters (ENT) [3]. Adenosine in the cytosol is either metabolized by adenosine kinase to form AMP or ade- nosine deaminase producing inosine [1]. As a result of these metabolic processes, the levels of extracellular adenosine are kept low in unstressed, healthy tissues. However, under pathological conditions, the balance between the formation and removal of adenosine is violated, which results in increased extracellular ade- nosine concentrations [1]. The physiological and pathophysiological effects of the endogenous natural ligand adenosine are medi- ated by four types of adenosine receptors (ARs): A 1 , Abbreviations: MOF, multiple organ failure; 5-LO, 5-lipoxige- nase; A 2A AR, adenosine A 2A receptor; AC, adenylate cyclase; AP-1, activator protein 1; AR, adenosine receptor; CD, cluster of differentiation (of lymphocytes); CDC42, cell division control pro- tein 42 homolog; CEBPβ, CCAAT-enhancer-binding protein; beta-COX-2, cycloxygenase of type 2; CREB1, cAMP respon- sive element binding protein 1; CTLA-4, cytotoxic T-lympho- cyte-associated antigen 4; CXCL, chemokine (C-X-C motif) ligand 1; eNOS, endothelial NO synthase; GCSF, granulocyte colony-stimulating factor; GPCR, G-protein-coupled receptor; ICAM-1, intercellular adhesion molecule 1; IFN, interferon; IL, interleukin; iNOS, inducible NO synthase; IP3, inositol 3,4,5-triphosphate; MAPK, mitogen-activated protein kinase; MCSF, macrophage colony-stimulating factor; MOF, multiple organ failure; NF-κB, nuclear factor κB; NOS, NO synthase; PAF, platelet activating factor; PAI-1, plasminogen activator inhib- itor-1; PDZ-GEF1, guanine nucleotide exchange factor containing PDZ-domain; PGE2, prostaglandin E2; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol 4,5-diphosphate; PKA, pro- tein kinase A; PKB (or Akt), protein kinase B; PKC-zeta, protein kinase С-zeta; SIRS, systemic inflammatory response syndrome; SUMO-1, small ubiquitin-related modifier 1; TF, tissue factor III (thromboplastin); TGF-β, transforming growth factor beta; TLRs, Toll-like receptors; TNF-α, tumor necrosis factor α; TRAX, translin-associated factor X; USP4, ubiquitin specific protease 4. 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