Vol. 299, Issue 1, 131-136, October 2001

Selective Agonism of Group I P2X Receptors by Dinucleotides Dependent on a Single Adenine Moiety

Okan Cinkilic , Brian F. King, Markus van der Giet, Hartmut Schlüter, Walter Zidek and Geoffrey Burnstock

Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, United Kingdom (O.C., B.F.K., G.B.); and Freie Universität Berlin, Medizinische Klinik IV, Universitätsklinikum Benjamin-Franklin, Berlin, Germany (O.C., M.v.d.G., H.S., W.Z.)

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 Xenopus laevis 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.