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Diinosine pentaphosphate (IP5I) is a potent antagonist at recombinant rat P2X(1) receptors

King, BF; Liu, M; Pintor, J; Gualix, J; Miras-Portugal, MT; Burnstock, G; (1999) Diinosine pentaphosphate (IP5I) is a potent antagonist at recombinant rat P2X(1) receptors. BRIT J PHARMACOL , 128 (5) 981 - 988.

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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 P2X(1-4) 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., Ap(5)A into Ip(5)I) using 5'-adenylic deaminase, and purified using reverse-phase chromatography.3 Against ATP-responses at rP2X(1) receptors, the potency order for antagonism was (pIC(50)): Ip(5)I (8.5) > Ip(4)I (6.3) > Ip(3)I (>4.5). Ip(5)I (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 Ip(5)I is not a competitive antagonist. Blockade by micromolar concentrations of Ip(5)I was not surmountable. Ip(4)I also behaved as a non-surmountable antagonist.4 Against ATP-responses at rP2X(3) receptors, the potency order for antagonism was (pIC(50)): Ip(4)I (6.0) > Ip(5)I (5.6) > Ip(3)I (>4.5). Blockade by Ip(4)I (pA(2), 6.75) and Ip(5)I (pA(2), 6.27) was surmountable at micromolar concentrations.5 Diinosine polyphosphates failed to inhibit ATP-responses at rP2X(2) receptors, whereas agonist responses at rP2X(4) were reversibly potentiated by Ip(4)I and Ip(5)I. None of the parent diadenosine polyphosphates behave as antagonists at rP2X(1-4) receptors.6 Thus, Ip(5)I acted as a potent and relatively-selective antagonist at the rP2X(1) receptor. This dinucleotide pentaphosphate represents a high-affinity antagonist for the P2X(1) receptor, at which it acts in a competitive manner at low (less than or equal to 100 nM) concentrations but has more complex actions at higher (>100 nM) concentrations.

Type: Article
Title: Diinosine pentaphosphate (IP5I) is a potent antagonist at recombinant rat P2X(1) receptors
Keywords: P2X receptor, ion channel, ATP, dinucleotide, Ip(5)I, diinosine polyphosphate, antagonist, Xenopus oocyte, GATED ION CHANNELS, P-2X PURINOCEPTORS, VAS-DEFERENS, ATP, DINUCLEOTIDES, SELECTIVITY, ACTIVATION, NEURONS
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/87339
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