Adenosine receptors of human leukocytes-II. Characterization of an inhibitory p-site

We have investigated the effects of 2′,5′-dideoxyadenosine (DDA), 9′-β-D-arabinofurano-syladenine (ARA), and 9-β-D-xylofuranosyladenine (XFA), which have been classified as P-site adenosine agonists, on the cyclic adenosine 3′,5′-monophosphate (cAMP) metabolism of human lymphocytes and polymorphonuclear leukocytes (PMNs). DDA (10^-5-2 × 10^-4M), ARA and XFA caused a dose-dependent decrease in cAMP content of human lymphocytes. In addition to decreasing lymphocyte cAMP levels, DDA, ARA and XFA markedly inhibited the effects of many adenylate cyclase-stimulating agents including β-adrenergic stimuli, prostaglandin E₁ (PGE₁), histamine, adenosine, forskolin and cholera toxin. Theophylline and 3-isobutyl-1-methylxanthine, which are known antagonists of adenosine A₁/R_i, and A₂/R_a, receptors, did not modify the inhibiting effects of DDA. Mn²⁺ (1 mM) increased the sensitivity to inhibition of adenylate cyclase agonists by DDA. We also searched for the presence of adenosine P-sites in human PMNs. DDA caused a significant decrease of PMN cAMP levels only at the highest concentrations used (Z × 10^-4M). In contrast, even low concentrations of DDA (10^-6-10^-4 M) concentration-dependently blocked the stimulatory effect of PGE₁ and forskolin on PMN cAMP accumulation. The results support the existence of a purine P-site that regulates cAMP metabolism of human lymphocytes and PMNs.