Selective agonism of group IP2X receptors by dinucleotides dependent on a single adenine moiety

We have investigated the activity of naturally occurring highperformance li quid chromatography-purified diadenosine polyphosphates (Ap(n)A, n = 5-6), adenosine polyphospho guanosines (AP(n)G, n = 5-6), and diguanosine polypho sphates (Gp(n)G, n = 5-6) under voltage-clamp conditions at recombinant rat P2X(1-4) purinoceptor subtypes expressed in Xenopus laevis oocytes. At rP2 X(1) and rP2X(3) receptors, Ap(n)As and AP(n)Gs evoked concentration-depend ent inward currents. Gp(n)Gs were not active at these receptors. At rP2X(2) and rP2X(4) receptors, dinucleotides did not show significant activity. Fo r the rP2X(1) receptor, AP(n)As and AP(n)Gs were partial agonists; for the P2X(3) receptor, only AP(5)G was full agonist, whereas the other tested sub stances were partial agonists. The rank order of potency at rP2X(1) was ATP greater than or equal to Ap(6)A greater than or equal to Ap(5)A greater th an or equal to Ap(6)G greater than or equal to Ap(5)G, and rank order of ef ficacy was ATP greater than or equal to Ap(5)A greater than or equal to Ap( 6)A > Ap(5)G > Ap(6)G, whereas at rP2X(3) the rank order of potency was ATP > Ap(5)G greater than or equal to Ap(5)A greater than or equal to Ap(6)A g reater than or equal to Ap(6)G and the rank order of efficacy was ATP appro ximate to Ap(5)G greater than or equal to Ap(5)A approximate to Ap(6)A grea ter than or equal to Ap(6)G. For rP2X(1) and rP2X(3) it is evident that rec eptor agonism depended on the presence of at least one adenine moiety in th e dinucleotide, while the presence of a guanine moiety had a significant im pact and decreased agonist efficacy. The data suggest that naturally occurr ing Ap,As and Ap,Gs may play an important physiological role in different h uman tissues and systems by activating group I P2X receptors.