Overview of extracellular nucleotide and nucleoside signaling. In the extracellular compartment, the purinergic nucleotide ATP and its metabolic offspring—the nucleoside adenosine—are known to function as signaling molecules. During conditions of cellular stress (such as occurs during ischemia and reperfusion or vascular inflammation), multiple cell types release ATP (and ADP) into the extracellular compartment. Extracellular ATP can function as a signaling molecule via activation of purinergic P2 receptors specifically through the family of P2Y receptors—G-protein–coupled receptors—or through the family of P2X receptors, ligand-gated ion channels. In addition to its role as a direct activator of P2 receptors, ATP also functions as the main metabolic precursor for the extracellular generation of adenosine. For this purpose, ATP is metabolized by enzymatic phosphohydrolysis in a two-step process via CD39 conversion of ATP (or ADP) to AMP, and subsequent phosphohydrolysis of AMP to adenosine by CD73. Similar to ATP, adenosine functions as a direct activator of purinergic receptors, which are classified as P1 receptors. Currently, 4 distinct P1 adenosine receptors are known: Adora1 (A1), Adora2a (A2A), Adora2b (A2B), and Adora3 (A3). Adenosine signaling is terminated by uptake of adenosine from the extracellular toward the intracellular compartment by ENTs (particularly ENT1 and ENT2), followed by subsequent metabolism to inosine by the adenosine deaminase (ADA) or phosphorylation by the adenosine kinase (AK) to AMP.