Extracellular adenosine signaling in molecular medicine
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Adenosine—a purinergic signaling molecule
Biochemically, adenosine belongs to a group of molecules referred to as purines. Purines are heterocyclic aromatic molecules that are among the oldest and most influential biochemical compounds in evolutionary history . They are critical building blocks of the genetic code, and therefore the substrate of life, as represented by DNA. These relatively simple molecules are composed from adenine and guanine, and without these molecules, life as we know it would not be possible . In a wide sense, purines are central to the self-sustained and reproducible existence of nucleotide–protein systems, which form cells and tissues that ultimately resulted in an appearance of Homo sapiens . As such, the purine adenosine is well recognized as molecular building block of the genetic code or as part of adenosine triphosphate (ATP)—the universal energy currency of biological reactions . Beyond these function, Alan Drury and Albert Szent-Györgyi from the University of Cambridge introduced in 1929 the idea that purines could also function as extracellular signaling molecules. They injected extracts from cardiac tissues intravenously into a whole animal. They observed a transient slowing of the heart rate . Following several purification steps, they came to the conclusion that the biologic activity in the extract was an “adenine compound” . Today, we have genetic evidence that the transient heart block induced by intravascular adenosine injection is mediated by the activation of an adenosine receptor [5, 6]. Indeed, adenosine signaling can occur through four distinct adenosine receptors—the Adora1, Adora2a, Adora2b, and Adora3—all of them G-protein-coupled receptors. Adenosine-induced heart block remains the most famous clinical application for adenosine signaling, as intravenous adenosine injection continues to be a mainstay therapy for the diagnosis and treatment of supraventricular tachycardia [7, 8].
The complex control of extracellular adenosine signaling
There are many control steps regulating extracellular adenosine signaling events, such as ATP release, its conversion to adenosine via CD39 and CD73, or the expression of adenosine receptors (Fig. 1). Moreover, there is evidence that alternative molecular pathways exist that can function to enhance extracellular adenosine signaling independent of adenosine, such as enhancement of purinergic signaling events through the neuronal guidance molecule netrin-1 [30, 31, 32]. Finally, the termination of extracellular adenosine signaling is a highly complex biological process with many steps that are independently regulated on a transcriptional level [33, 34, 35]. As such, adenosine is taken up from the extracellular into the intracellular compartment through adenosine transporters , and subsequently converted to inosine via the adenosine deaminase [36, 37], or via the adenosine kinase to AMP (Fig. 1) . These processes can function together to fine-tune extracellular adenosine levels and signaling functions .
Extracellular adenosine signaling during disease states
As such, there are numerous examples for the importance of extracellular adenosine signaling in molecular medicine. In most instances, extracellular adenosine signaling has anti-inflammatory functions during acute disease states, such as acute lung injury, ischemia and reperfusion, or intestinal inflammation [7, 48]. Under such circumstances, pharmacologic approaches to enhance adenosine signaling effects (e.g., via adenosine receptor agonists or adenosine uptake inhibitors) are investigated in preclinical studies [50, 51, 53]. In contrast, adenosine-elicited inhibition of immune responses during neoplastic disease states contributes to tumor growth and metastasis, thereby implicating adenosine receptor blockers in the treatment of cancer . Similarly, inhibition of adenosine receptors is an evolving therapeutic concept for the treatment chronic disease states, such as pulmonary fibrosis or sickle cell disease. Here, it will be particularly important to identify biomarkers that will help physicians to judge when adenosine protection during an acute disease states turns into promoting its chronicity . Much work will be required to determine the clinical contexts in which the activation or inhibition of specific adenosine receptors can be utilized therapeutically to improve outcomes of acute and chronic inflammatory diseases states, ischemia and reperfusion injury, or cancer. The five articles in this special issue of The Journal of Molecular Medicine [49, 50, 51, 52, 53] provide a roadmap for further exploration of the field of purinergic signaling for the treatment of human disease states.
The present research work was supported by National Heart Institute Grants R01-HL0921, R01-DK083385, and R01-HL098294 and a grant by the Crohn’s and Colitis Foundation of America to H. K. E.
Conflict of interest
The author has declared no conflict of interest.
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