Extracellular nucleotides

Extracellular nucleotides, including adenosine triphosphate (ATP), adenosine diphosphate (ADP), and uridine nucleotides (UTP, UDP), act as essential signaling molecules in the purinergic signaling pathway [2, 4]. They are released from cells through specialized channels like pannexin-1, vesicular exocytosis, or following tissue damage, where they function as damage-associated molecular patterns (DAMPs) to modulate immune responses and maintain tissue homeostasis [6, 11]. These molecules trigger biological responses by binding to two main classes of cell-surface receptors: ionotropic P2X receptors and metabotropic G-protein-coupled P2Y receptors [4, 14]. The activity and concentration of extracellular nucleotides are tightly regulated by ectonucleotidases such as CD39 and CD73, which metabolize them into adenosine, effectively shifting the extracellular signaling environment from pro-inflammatory to immunosuppressive [1, 5, 13]. Dysregulation of extracellular nucleotide signaling is implicated in various pathological conditions, including chronic inflammation, thrombosis, and cancer [2, 9]. In the tumor microenvironment, the conversion of extracellular nucleotides into adenosine promotes tumor evasion by suppressing anti-tumor immunity [1, 14]. Current therapeutic strategies include blocking specific receptors, such as the P2Y12 receptor for antithrombotic therapy or the P2X3 receptor for chronic cough, as well as inhibiting ectonucleotidases like CD73 to relieve immunosuppression in oncology [12, 14]. Thus, while often considered as a class of ligands, extracellular nucleotides and their metabolic pathway represent a critical therapeutic target axis across multiple medical disciplines [3, 11].

Other names

Extracellular ATPExtracellular purinesExtracellular pyrimidineseATPPurinergic signaling ligandsDamage-associated molecular patterns (DAMPs)

Modulation of purinergic signaling through the antagonism of P2X and P2Y receptors, inhibition of ectonucleotidase enzymes (CD39/CD73) to alter nucleotide-to-nucleoside conversion, or direct enzymatic degradation of nucleotides in the extracellular space.