Abstract

We have investigated the activity of naturally occurring high-performance liquid chromatography-purified diadenosine polyphosphates (Ap_nA, n = 5–6), adenosine polyphospho guanosines (Ap_nG,n = 5–6), and diguanosine polyphosphates (Gp_nG, n = 5–6) under voltage-clamp conditions at recombinant rat P2X_1–4 purinoceptor subtypes expressed in Xenopuslaevis oocytes. At rP2X₁ and rP2X₃ receptors, Ap_nAs and Ap_nGs evoked concentration-dependent inward currents. Gp_nGs were not active at these receptors. At rP2X₂ and rP2X₄ receptors, dinucleotides did not show significant activity. For the rP2X₁ receptor, Ap_nAs and Ap_nGs were partial agonists; for the P2X₃ receptor, only Ap₅G was full agonist, whereas the other tested substances were partial agonists. The rank order of potency at rP2X₁ was ATP ≥ Ap₆A ≥ Ap₅A ≥ Ap₆G ≥ Ap₅G, and rank order of efficacy was ATP ≥ Ap₅A ≥ Ap₆A > Ap₅G > Ap₆G, whereas at rP2X₃ the rank order of potency was ATP > Ap₅G ≥ Ap₅A ≥ Ap₆A ≥ Ap₆G and the rank order of efficacy was ATP ≈ Ap₅G ≥ Ap₅A ≈ Ap₆A ≥ Ap₆G. For rP2X₁ and rP2X₃ it is evident that receptor agonism depended on the presence of at least one adenine moiety in the dinucleotide, while the presence of a guanine moiety had a significant impact and decreased agonist efficacy. The data suggest that naturally occurring Ap_nAs and Ap_nGs may play an important physiological role in different human tissues and systems by activating group I P2X receptors.