%0 Journal Article %J Molecular pharmacology. 2006 Jul; 70(1):373-82 %D 2006 %T Experimental and modeling studies of desensitization of P2X3 receptors. %A Elena Sokolova %A Andrei Skorinkin %A Igor Moiseev %A Andrei A. Agrachev %A Andrea Nistri %A Rashid Giniatullin %X 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 microM 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 beta,gamma-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. %B Molecular pharmacology. 2006 Jul; 70(1):373-82 %I the American Society for Pharmacology and Experimental Therapeutics %G en %U http://hdl.handle.net/1963/4974 %1 4799 %2 Neuroscience %3 Neurobiology %4 -1 %$ Submitted by Alireza Alemi-neissi (alemi@sissa.it) on 2011-10-30T18:23:32Z\\nNo. of bitstreams: 0 %R 10.1124/mol.106.023564