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Experimental and Modeling Studies of Desensitization of P2X₃ Receptors

Sectors of Neurobiology (E.S., A.S., A.N., R.G.) and Functional Analysis (I.M., A.A.) and Consiglio Nazionale delle Ricerche-Istituto Nazionale per la Fisica della Materia Democritos Modeling Center for Research in Atomistic Stimulation National Simulation Center, International School for Advanced Studies, Trieste, Italy (E.S., A.N., R.G.); Biochemical and Biophysical Institute of the Russian Academy of Sciences, Kazan, Russia (A.S.); and Kazan Medical University, Kazan, Russia (R.G.)

The function of ATP-activated P2X₃ receptors involved in pain sensation is modulated by desensitization, a phenomenon poorly understood. The present study used patch-clamp recording from cultured rat or mouse sensory neurons and kinetic modeling to clarify the properties of P2X₃ receptor desensitization. Two types of desensitization were observed, a fast process (t_1/2 = 50 ms; 10 µM ATP) following the inward current evoked by micromolar agonist concentrations, and a slow process (t_1/2 = 35 s; 10 nM ATP) that inhibited receptors without activating them. We termed the latter high-affinity desensitization (HAD). Recovery from fast desensitization or HAD was slow and agonist-dependent. When comparing several agonists, there was analogous ranking order for agonist potency, rate of desensitization and HAD effectiveness, with 2-methylthioadenosine triphosphate the strongest and ,-methylene-ATP the weakest. HAD was less developed with recombinant (ATP IC₅₀ = 390 nM) than native P2X₃ receptors (IC₅₀ = 2.3 nM). HAD could also be induced by nanomolar ATP when receptors seemed to be nondesensitized, indicating that resting receptors could express high-affinity binding sites. Desensitization properties were well accounted for by a cyclic model in which receptors could be desensitized from either open or closed states. Recovery was assumed to be a multistate process with distinct kinetics dependent on the agonist-dependent dissociation rate from desensitized receptors. Thus, the combination of agonist-specific mechanisms such as desensitization onset, HAD, and resensitization could shape responsiveness of sensory neurons to P2X₃ receptor agonists. By using subthreshold concentrations of an HAD-potent agonist, it might be possible to generate sustained inhibition of P2X₃ receptors for controlling chronic pain.

Address correspondence to: Dr. R. Giniatullin, International School for Advanced Studies, Via Beirut 4, 34104 Trieste, Italy. E-mail: rashid{at}sissa.it

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