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Experimental and modeling studies of desensitization of P2X3 receptors.
Mol Pharmacol 2006; 70(1):373-82MP

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 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.

Authors+Show Affiliations

International School for Advanced Studies, Via Beirut 4, 34104 Trieste, Italy.

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16627751

Citation

Sokolova, Elena, et al. "Experimental and Modeling Studies of Desensitization of P2X3 Receptors." Molecular Pharmacology, vol. 70, no. 1, 2006, pp. 373-82.
Sokolova E, Skorinkin A, Moiseev I, et al. Experimental and modeling studies of desensitization of P2X3 receptors. Mol Pharmacol. 2006;70(1):373-82.
Sokolova, E., Skorinkin, A., Moiseev, I., Agrachev, A., Nistri, A., & Giniatullin, R. (2006). Experimental and modeling studies of desensitization of P2X3 receptors. Molecular Pharmacology, 70(1), pp. 373-82.
Sokolova E, et al. Experimental and Modeling Studies of Desensitization of P2X3 Receptors. Mol Pharmacol. 2006;70(1):373-82. PubMed PMID: 16627751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Experimental and modeling studies of desensitization of P2X3 receptors. AU - Sokolova,Elena, AU - Skorinkin,Andrei, AU - Moiseev,Igor, AU - Agrachev,Andrei, AU - Nistri,Andrea, AU - Giniatullin,Rashid, Y1 - 2006/04/20/ PY - 2006/4/22/pubmed PY - 2006/10/25/medline PY - 2006/4/22/entrez SP - 373 EP - 82 JF - Molecular pharmacology JO - Mol. Pharmacol. VL - 70 IS - 1 N2 - 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. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/16627751/Experimental_and_modeling_studies_of_desensitization_of_P2X3_receptors_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16627751 DB - PRIME DP - Unbound Medicine ER -