Adenosine

The rhizome of Typhonium giganteum Engl.

Adenosine is a nucleoside composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a β-N9-glycosidic bond.

Adenosine transiently modulates stimulated dopamine release in the caudate-putamen via A1 receptors.[Pubmed:25219576]

J Neurochem. 2015 Jan;132(1):51-60.

Adenosine modulates dopamine in the brain via A1 and A2A receptors, but that modulation has only been characterized on a slow time scale. Recent studies have characterized a rapid signaling mode of Adenosine that suggests a possible rapid modulatory role. Here, fast-scan cyclic voltammetry was used to characterize the extent to which transient Adenosine changes modulate stimulated dopamine release (5 pulses at 60 Hz) in rat caudate-putamen brain slices. Exogenous Adenosine was applied and dopamine concentration monitored. Adenosine only modulated dopamine when it was applied 2 or 5 s before stimulation. Longer time intervals and bath application of 5 muM Adenosine did not decrease dopamine release. Mechanical stimulation of endogenous Adenosine 2 s before dopamine stimulation also decreased stimulated dopamine release by 41 +/- 7%, similar to the 54 +/- 6% decrease in dopamine after exogenous Adenosine application. Dopamine inhibition by transient Adenosine was recovered within 10 min. The A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine blocked the dopamine modulation, whereas dopamine modulation was unaffected by the A2A receptor antagonist SCH 442416. Thus, transient Adenosine changes can transiently modulate phasic dopamine release via A1 receptors. These data demonstrate that Adenosine has a rapid, but transient, modulatory role in the brain. Here, transient Adenosine was shown to modulate phasic dopamine release on the order of seconds by acting at the A1 receptor. However, sustained increases in Adenosine did not regulate phasic dopamine release. This study demonstrates for the first time a transient, neuromodulatory function of rapid Adenosine to regulate rapid neurotransmitter release.

Elevated placental adenosine signaling contributes to the pathogenesis of preeclampsia.[Pubmed:25538227]

Circulation. 2015 Feb 24;131(8):730-41.

BACKGROUND: Preeclampsia is a prevalent hypertensive disorder of pregnancy and a leading cause of maternal and neonatal morbidity and mortality worldwide. This pathogenic condition is speculated to be caused by placental abnormalities that contribute to the maternal syndrome. However, the specific factors and signaling pathways that lead to impaired placentas and maternal disease development remain elusive. METHODS AND RESULTS: Using 2 independent animal models of preeclampsia (genetically engineered pregnant mice with elevated Adenosine exclusively in placentas and a pathogenic autoantibody-induced preeclampsia mouse model), we demonstrated that chronically elevated placental Adenosine was sufficient to induce hallmark features of preeclampsia, including hypertension, proteinuria, small fetuses, and impaired placental vasculature. Genetic and pharmacological approaches revealed that elevated placental Adenosine coupled with excessive A(2)B Adenosine receptor (ADORA2B) signaling contributed to the development of these features of preeclampsia. Mechanistically, we provided both human and mouse evidence that elevated placental CD73 is a key enzyme causing increased placental Adenosine, thereby contributing to preeclampsia. CONCLUSIONS: We determined that elevated placental Adenosine signaling is a previously unrecognized pathogenic factor for preeclampsia. Moreover, our findings revealed the molecular basis underlying the elevation of placental Adenosine and the detrimental role of excess placental Adenosine in the pathophysiology of preeclampsia, and thereby, we highlight novel therapeutic targets.

Down-regulation of the A3 adenosine receptor in human mast cells upregulates mediators of angiogenesis and remodeling.[Pubmed:25597247]

Mol Immunol. 2015 May;65(1):25-33.

Adenosine activated mast cells have been long implicated in allergic asthma and studies in rodent mast cells have assigned the A3 Adenosine receptor (A3R) a primary role in mediating Adenosine responses. Here we analyzed the functional impact of A3R activation on genes that are implicated in tissue remodeling in severe asthma in the human mast cell line HMC-1 that shares similarities with lung derived human mast cells. Quantitative real time PCR demonstrated upregulation of IL6, IL8, VEGF, amphiregulin and osteopontin. Moreover, further upregulation of these genes was noted upon the addition of dexamethasone. Unexpectedly, activated A3R down regulated its own expression and knockdown of the receptor replicated the pattern of agonist induced gene upregulation. This study therefore identifies the human mast cell A3R as regulator of tissue remodeling gene expression in human mast cells and demonstrates a heretofore-unrecognized mode of feedback regulation that is exerted by this receptor.

Elevated adenosine signaling via adenosine A2B receptor induces normal and sickle erythrocyte sphingosine kinase 1 activity.[Pubmed:25587035]

Blood. 2015 Mar 5;125(10):1643-52.

Erythrocyte possesses high sphingosine kinase 1 (SphK1) activity and is the major cell type supplying plasma sphingosine-1-phosphate, a signaling lipid regulating multiple physiological and pathological functions. Recent studies revealed that erythrocyte SphK1 activity is upregulated in sickle cell disease (SCD) and contributes to sickling and disease progression. However, how erythrocyte SphK1 activity is regulated remains unknown. Here we report that Adenosine induces SphK1 activity in human and mouse sickle and normal erythrocytes in vitro. Next, using 4 Adenosine receptor-deficient mice and pharmacological approaches, we determined that the A2B Adenosine receptor (ADORA2B) is essential for Adenosine-induced SphK1 activity in human and mouse normal and sickle erythrocytes in vitro. Subsequently, we provide in vivo genetic evidence that Adenosine deaminase (ADA) deficiency leads to excess plasma Adenosine and elevated erythrocyte SphK1 activity. Lowering Adenosine by ADA enzyme therapy or genetic deletion of ADORA2B significantly reduced excess Adenosine-induced erythrocyte SphK1 activity in ADA-deficient mice. Finally, we revealed that protein kinase A-mediated extracellular signal-regulated kinase 1/2 activation functioning downstream of ADORA2B underlies Adenosine-induced erythrocyte SphK1 activity. Overall, our findings reveal a novel signaling network regulating erythrocyte SphK1 and highlight innovative mechanisms regulating SphK1 activity in normal and SCD.

Modulation of neuroimmunity by adenosine and its receptors: metabolism to mental illness.[Pubmed:25308443]

Metabolism. 2014 Dec;63(12):1491-8.

Adenosine is a pleiotropic bioactive with potent neuromodulatory properties. Due to its ability to easily cross the blood-brain barrier, it can act as a signaling molecule between the periphery and the brain. It functions through four (A1, A2A, A2B, and A3) cell surface G protein-coupled Adenosine receptors (ARs) that are expressed in some combination on nearly all cells types within the CNS. By regulating the activity of adenylyl cyclase and changing the intracellular concentration of cAMP, Adenosine can alter neuronal function and neurotransmission. A variety of illnesses related to metabolic dysregulation, such as type 1 diabetes and Alzheimer's disease, are associated with an elevated serum concentration of Adenosine and a pathogenesis rooted in inflammation. This review describes the accepted physiologic function of Adenosine in neurological disease and explores its new potential as a peripheral to central danger signal that can activate the neuroimmune system and contribute to symptoms of sickness and psychopathologies.

Adenosine receptors as therapeutic targets.[Pubmed:16518376]

Nat Rev Drug Discov. 2006 Mar;5(3):247-64.

Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of Adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various Adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of Adenosine receptor modulators considerably closer.

Adenosine is a nucleoside composed of a molecule of adenine attached to a ribose sugar molecule (ribofuranose) moiety via a β-N9-glycosidic bond.

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