Selective agonism of group I P2X receptors by dinucleotides dependent on a single adenine moiety

TY - JOUR

T1 - Selective agonism of group I P2X receptors by dinucleotides dependent on a single adenine moiety

AU - Cinkilic, O

AU - King, B F

AU - van der Giet, M

AU - Schlüter, H

AU - Zidek, W

AU - Burnstock, G

PY - 2001/10

Y1 - 2001/10

N2 - 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.

AB - 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.

KW - Adenine

KW - Animals

KW - Humans

KW - Membrane Potentials

KW - Nucleotides

KW - Oocytes

KW - Patch-Clamp Techniques

KW - Purinergic P2 Receptor Agonists

KW - Receptors, Purinergic P2X

KW - Receptors, Purinergic P2X3

KW - Receptors, Purinergic P2X4

KW - Recombinant Proteins

KW - Structure-Activity Relationship

KW - Vasoconstrictor Agents

KW - Xenopus laevis

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

M3 - SCORING: Journal article

C2 - 11561072

VL - 299

SP - 131

EP - 136

JO - J PHARMACOL EXP THER

JF - J PHARMACOL EXP THER

SN - 0022-3565

IS - 1

ER -