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

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

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), 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 -