Abstract
We have investigated the activity of naturally occurring high-performance liquid chromatography-purified diadenosine polyphosphates (ApnA, n = 5–6), adenosine polyphospho guanosines (ApnG,n = 5–6), and diguanosine polyphosphates (GpnG, n = 5–6) under voltage-clamp conditions at recombinant rat P2X1–4 purinoceptor subtypes expressed in Xenopuslaevis oocytes. At rP2X1 and rP2X3 receptors, ApnAs and ApnGs evoked concentration-dependent inward currents. GpnGs were not active at these receptors. At rP2X2 and rP2X4 receptors, dinucleotides did not show significant activity. For the rP2X1 receptor, ApnAs and ApnGs 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 ApnAs and ApnGs may play an important physiological role in different human tissues and systems by activating group I P2X receptors.
Footnotes
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This work was supported by the Deutsche Forschungs-gemeinschatft (Grant Schl 406/1-2) and by Roche Bioscience.
- Abbreviations:
- ApnA
- diadenosine polyphosphate
- ApnG
- polyphospho guanosine
- Ap6A
- diadenosine hexaphosphate
- α
- β-meATP, α, β-methylene-adenosine 5'-triphosphate
- GpnG
- diguanosine polyphosphate
- Ap5A
- diadenosine pentaphosphate
- Ap5G
- adenosine pentaphospho guanosine
- Ap6G
- adenosine hexaphospho guanosine
- Gp5G
- diguanosine pentaphosphate
- Gp6G
- diguanosine hexaphosphate
- Received February 28, 2001.
- Accepted June 11, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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