Extracellular adenosine signaling in molecular medicine

Abstract

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 [1]. 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 [2]. 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 [2]. 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 [3]. Beyond these function, Alan Drury and Albert Szent-Gyorgyi 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 [4]. Following several purification steps, they came to the conclusion that the biologic activity in the extract was an “adenine compound” [4]. 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].