Diinosine pentaphosphate: an antagonist which discriminates between recombinant P2X(3) and P2X(2/3) receptors and between two P2X receptors in rat sensory neurones

1 We have compared the antagonist activity of trinitrophenyl-ATP (TNP-ATP) and diinosine pentaphosphate (Ip(5)I) on recombinant P2X receptors expresse d in Xenopus oocytes with their actions at native P2X receptors in sensory neurones from dorsal root and nodose ganglia. 2 Slowly-desensitizing responses to alpha,beta-methyfene, ATP (alpha,beta-m eATP) recorded from oocytes expressing P2X(2/3) receptors were inhibited by TNP-ATP at sub-micromolar concentrations. However, Ip(5)I at concentration s up to 30 mu M was without effect. 3 Nodose ganglion neurones responded to alpha,beta-meATP with slowly-desens itizing inward currents. These were inhibited by TNP-ATP (IC50, 20 nM), but not by Ip(5)I at concentrations up to 30 mu M. 4 In DRG neurones that responded to ATP with a rapidly-desensitizing inward current, the response was inhibited by TNP-ATP with an IC50 of 0.8 nM. The se responses were also inhibited by Ip(5)I with an IC50 of 0.1 mu M. Both a ntagonists an known to inhibit homomeric P2X(3) receptors. 5 Some DRG neurones responded to alpha,beta-meATP with a biphasic inward cu rrent, consisting of transient and sustained components. While the transien t current was abolished by 1 mu M Ip(5)I, the sustained component remained unaffected. 6 In conclusion, Ip(5)I is a potent antagonist at homomeric P2X3 receptors but not at heteromeric P2Y(2/3) receptors, and therefore should be a useful tool for elucidating the subunit composition of native P2X receptors.