title: Selective agonism of group I P2X receptors by dinucleotides dependent on a single adenine moiety.
abstract: We have investigated the activity of naturally occurring high-performance liquid chromatography-purified diadenosine polyphosphates (Ap(n)A, n = 5-6), adenosine polyphospho guanosines (Ap(n)G, n = 5-6), and diguanosine polyphosphates (Gp(n)G, n = 5-6) under voltage-clamp conditions at recombinant rat P2X1-4 purinoceptor subtypes expressed in Xenopus laevis oocytes. At rP2X1 and rP2X3 receptors, Ap(n)As and Ap(n)Gs evoked concentration-dependent inward currents. Gp(n)Gs were not active at these receptors. At rP2X2 and rP2X4 receptors, dinucleotides did not show significant activity. For the rP2X1 receptor, Ap(n)As and Ap(n)Gs 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 > or = Ap6A > or = Ap5A > or = Ap6G > or = Ap5G, and rank order of efficacy was ATP > or = Ap5A > or = Ap6A > Ap5G > Ap6G, whereas at rP2X3 the rank order of potency was ATP > Ap5G > or = Ap5A > or = Ap6A > or = Ap6G and the rank order of efficacy was ATP approximately Ap5G > or = Ap5A approximately Ap6A > or = 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(n)As and Ap(n)Gs may play an important physiological role in different human tissues and systems by activating group I P2X receptors.
authors.affiliation: Autonomic Neuroscience Institute, Royal Free and University College Medical School, London, United Kingdom.
authors.forename: O
authors.initials: O
authors.lastname: Cinkilic
authors.forename: B F
authors.initials: BF
authors.lastname: King
authors.forename: M
authors.initials: M
authors.lastname: van der Giet
authors.forename: H
authors.initials: H
authors.lastname: Schlüter
authors.forename: W
authors.initials: W
authors.lastname: Zidek
authors.forename: G
authors.initials: G
authors.lastname: Burnstock
mesh_terms: D000225:Adenine / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D009711:Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D058910:Purinergic P2 Receptor Agonists; D058469:Receptors, Purinergic P2X; D058477:Receptors, Purinergic P2X3; D058848:Receptors, Purinergic P2X4; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D009711:Nucleotides; C546407:P2RX3 protein, human; C548226:P2RX4 protein, human; C546410:P2rx3 protein, rat; C548228:P2rx4 protein, rat; D058910:Purinergic P2 Receptor Agonists; D058469:Receptors, Purinergic P2X; D058477:Receptors, Purinergic P2X3; D058848:Receptors, Purinergic P2X4; D011994:Recombinant Proteins; D014662:Vasoconstrictor Agents; D000225:Adenine