Received for publication February 16, 2006.
Revised April 20, 2006.
Accepted for publication April 20, 2006.

Experimental and modeling studies of desensitization of P2X₃ receptors

Abstract

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 modelling 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-Me-SATP the strongest and ,-meATP 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 appeared to be non-desensitized, 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 multi-state 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.

Key words: Purinergic, Purinergic, Structure-activity relationships and modeling, Thermodynamic and kinetic processes and modeling, Func. analysis receptor/ion channel mutants

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