PT - JOURNAL ARTICLE AU - Elena Sokolova AU - Andrei Skorinkin AU - Igor Moiseev AU - Andrei Agrachev AU - Andrea Nistri AU - Rashid Giniatullin TI - Experimental and Modeling Studies of Desensitization of P2X<sub>3</sub> Receptors AID - 10.1124/mol.106.023564 DP - 2006 Jul 01 TA - Molecular Pharmacology PG - 373--382 VI - 70 IP - 1 4099 - http://molpharm.aspetjournals.org/content/70/1/373.short 4100 - http://molpharm.aspetjournals.org/content/70/1/373.full SO - Mol Pharmacol2006 Jul 01; 70 AB - 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 β,γ-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.