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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 (t1/2 = 50 ms; 10 µM ATP) following the inward current evoked by micromolar agonist concentrations, and a slow process (t1/2 = 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.
Received for publication February 16, 2006.
Accepted for publication April 20, 2006.
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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