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Diinosine pentaphosphate (IP<inf>5</inf>I) is a potent antagonist at recombinant rat P2X<inf>1</inf> receptors

King, BF; Liu, M; Pintor, J; Gualix, J; Miras-Portugal, MT; Burnstock, G; (1999) Diinosine pentaphosphate (IP<inf>5</inf>I) is a potent antagonist at recombinant rat P2X<inf>1</inf> receptors. British Journal of Pharmacology , 128 (5) pp. 981-988. 10.1038/sj.bjp.0702876.

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Abstract

1. The antagonist activity of a series of diinosine polyphosphates (Ip(n)I, where n = 3, 4, 5) was assessed against ATP-activated inward currents at rat P2X1-4 receptors expressed in Xenopus oocytes and studied under voltage-clamp conditions. 2. Diinosine polyphosphates were prepared by the enzymatic degradation of their corresponding diadenosine polyphosphates (e.g., Ap5A into Ip5I) using 5'-adenylic deaminase, and purified using reverse-phase chromatography. 3. Against ATP-responses at rP2X1 receptors, the potency order for antagonism was (pIC50): Ip5I (8.5) > Ip4I (6.3) > Ip3I (> 4.5). Ip5I (10-100 nM) caused a concentration-dependent rightwards displacement of the ATP concentration-response curve without reducing the maximum ATP effect. However, the Schild plot was non-linear which indicated Ip5I is not a competitive antagonist. Blockade by micromolar concentrations of Ip5I was not surmountable. Ip4I also behaved as a nonsurmountable antagonist. 4. Against ATP-responses at rP2X3 receptors, the potency order for antagonism was (pIC50): Ip4I (6.0) > Ip5I (5.6) > Ip3I (> 4.5). Blockade by Ip4I (pA2, 6.75) and Ip5I (pA2, 6.27) was surmountable at micromolar concentrations. 5. Diinosine polyphosphates failed to inhibit ATP-responses at rP2X2 receptors, whereas agonist responses at rP2X4 were reversibly potentiated by Ip4I and Ip5I. None of the parent diadenosine polyphosphates behave as antagonists at rP2X1-4 receptors. 6. Thus, Ip5I acted as a potent and relatively-selective antagonist at the rP2X1 receptor. This dinucleotide pentaphosphate represents a high-affinity antagonist for the P2X1 receptor, at which it acts in a competitive manner at low (≤ 100 nM) concentrations but has more complex actions at higher (> 100 nM) concentrations.

Type: Article
Title: Diinosine pentaphosphate (IP<inf>5</inf>I) is a potent antagonist at recombinant rat P2X<inf>1</inf> receptors
DOI: 10.1038/sj.bjp.0702876
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/22246
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