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The Journal of Neuroscience, August 10, 2005, 25(32):7359-7365; doi:10.1523/JNEUROSCI.5189-04.2005

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Cellular/Molecular
Use-Dependent Inhibition of P2X₃ Receptors by Nanomolar Agonist

Emily B. Pratt,¹ Thaddeus S. Brink,² Pamela Bergson,² Mark M. Voigt,³ and Sean P. Cook²

¹Oregon Health and Science University L-106, Portland, Oregon 97201-3098, ²Department of Anesthesia and Critical Care MC4028, University of Chicago, Chicago, Illinois 60637, and ³Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104

P2X₃ receptors desensitize within 100 ms of channel activation, yet recovery from desensitization requires several minutes. The molecular basis for this slow rate of recovery is unknown. We designed experiments to test the hypothesis that this slow recovery is attributable to the high affinity (< 1 nM) of desensitized P2X₃ receptors for agonist. We found that agonist binding to the desensitized state provided a mechanism for potent inhibition of P2X₃ current. Sustained applications of 0.5 nM ATP inhibited >50% of current to repetitive applications of P2X₃ agonist. Inhibition occurred at 1000-fold lower agonist concentrations than required for channel activation and showed strong use dependence. No inhibition occurred without previous activation and desensitization. Our data are consistent with a model whereby inhibition of P2X₃ by nanomolar [agonist] occurs by the rebinding of agonist to desensitized channels before recovery from desensitization. For several ATP analogs, the concentration required to inhibit P2X₃ current inversely correlated with the rate of recovery from desensitization. This indicates that the affinity of the desensitized state and recovery rate primarily depend on the rate of agonist unbinding. Consistent with this hypothesis, unbinding of [³²P]ATP from desensitized P2X₃ receptors mirrored the rate of recovery from desensitization. As expected, disruption of agonist binding by site-directed mutagenesis increased the IC₅₀ for inhibition and increased the rate of recovery.

Key words: purinergic; desensitization; recovery; ATP; nociceptor; ligand-gated

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Received Dec 20, 2004; revised June 30, 2005; accepted June 30, 2005.

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