Genoprotective Pathways. Part I. Extracellular Signaling Through G(s) Protein-coupled Adenosine Receptors Prevents Oxidative DNA Damage

Adenosine has been previously shown to be a cytoprotective paracrine released by injured cells. However, it is presently unknown whether extracellular adenosine can prevent DNA damage. We show here that the adenosine analog, 2-chloroadenosine (2CA), has a potent (IC(50)=2.04 x 10(-9)M) genoprotective effect in cells subsequently exposed to H(2)O(2). The genoprotective signaling is transduced through adenosine receptors of the A2a and A2b subtypes. Increasing [cAMP](i) by forskolin or by cell permeable 8-br-cAMP produced a similar effect, whereas inhibiting the cAMP-mediated pathway with H-89, or increasing [nitric oxide](i) or [cGMP](i) blocked 2CA effect. Proteasomal inhibitors had no impact on 2CA signaling, while lithium chloride, an inhibitor of glycogen synthase kinase 3beta, completely blocked 2CA-induced genoprotective effect. These data indicate for the first time that extracellular adenosine protects cells against imminent oxidative DNA damage and suggest that prophylactic activation of this pathway prior to genotoxic challenges might reduce mutation rates.