Modulatory activity of extracellular H+ and Zn2+ on ATP‐responses at rP2X1 and rP2X3 receptors

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Abstract
The modulatory activity of extracellular H+ and Zn2+ was examined on ATP‐responses at rat P2X1 (rP2X1) and rat P2X3 (rP2X3) receptors expressed in Xenopus oocytes and studied under voltage‐clamp conditions. Superfused ATP (0.03–30 μM, at pH 7.5) evoked inward currents at rP2X1 receptors (EC50 value, 300±7 nM). ATP potency was reduced 2 fold at pH 6.5, and 6 fold at pH 5.5, without altering the maximum ATP effect. Alkaline conditions (pH 8.0) did not alter ATP activity. Superfused ATP (0.01–300 μM, at pH 7.5) evoked inward currents at rP2X3 receptors (EC50 value, 1.8±0.3 μM). ATP activity was affected only at pH 5.5, reducing agonist potency 15 fold without altering the maximum ATP effect. Extracellular Zn2+ inhibited ATP‐responses at rP2X1 receptors in a time‐dependent manner, a 20 min pre‐incubation being optimal (IC50 value, 1.0±0.2 μM). However, the Zn2+ effect was pH‐independent, suggesting Zn2+‐ and H+‐inhibition of ATP‐responses occur through independent processes. Extracellular Zn2+ weakly potentiated ATP‐responses at rP2X3 receptors (EC50 value, 11±1 μM). The Zn2+ effect was dependent on pre‐incubation time and, with 20 min pre‐incubation periods, Zn2+ potentiated then inhibited ATP‐responses in a concentration‐dependent, but pH‐independent, manner. In summary, ATP activity at rP2X1 receptors was decreased by both extracellular H+ and Zn2+ and their effects were additive. ATP activity at rP2X3 receptors was less sensitive to H+‐inhibition and, in contrast, was potentiated by Zn2+ in a pH‐independent manner. These differential effects may help distinguish P2X1 and P2X3 receptors in whole tissues. British Journal of Pharmacology (1999) 128, 486–492; doi:10.1038/sj.bjp.0702802