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Molecular Pharmacology

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Research ArticleArticle

The Unusual State-Dependent Affinity of P2X3 Receptors Can Be Explained by an Allosteric Two-Open-State Model

R. Karoly, A. Mike, P. Illes and Z. Gerevich
Molecular Pharmacology January 2008, 73 (1) 224-234; DOI: https://doi.org/10.1124/mol.107.038901
R. Karoly
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A. Mike
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P. Illes
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Z. Gerevich
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Abstract

High-affinity desensitization (HAD) by nanomolar agonists was described to shape the ability of P2X3 receptors for mediating pain sensation. These receptors are activated by micromolar ATP, but nanomolar ATP is sufficient to effectively desensitize them. The mechanism behind HAD is still obscure. It has been suggested (

J Neurosci:-7365, 2005

) that HAD can happen only if the receptor has previously been activated and desensitized by high agonist concentrations. It was not clear, however, whether the high-affinity site was different from the conventional binding site and which mechanism led to its exposure during desensitization. A subsequent article (

Mol Pharmacol:-382, 2006

) argued that HAD could also occur without preceding desensitization, because even resting receptors expose high-affinity binding sites. To support this hypothesis, a kinetic model was proposed that could reproduce all major phenomena observed experimentally. We attempted to improve this model and used it to simulate the agonist-induced formation of the high-affinity binding site. We collected electrophysiological data using HEK 293 cells expressing human P2X3 receptors and fitted simulated currents to experimentally acquired currents. A simple allosteric kinetic model in which only triliganded receptors could open failed to reproduce receptor behavior; introduction of an additional diliganded open state was necessary. Simulation with this model gave results that were in good agreement with experimental data. By using simulations and experiments, we analyzed the process of high-affinity binding site formation upon agonist exposure and propose an explanation, which helps to resolve the apparent conflict regarding the mechanism of HAD.

Footnotes

  • This work was supported by grants from the Deutsche Forschungsgemeinschaft (IL 20/11-3) and the Hungarian Research Fund (T 037659). A.M. is the recipient of a Janos Bolyai Research Fellowship.

  • ABBREVIATIONS: HEK, human embryonic kidney; HAD, high-affinity desensitization; meATP, methylene ATP; MWC, Monod-Wyman-Changeux.

    • Received June 11, 2007.
    • Accepted October 9, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (1)
Molecular Pharmacology
Vol. 73, Issue 1
1 Jan 2008
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Research ArticleArticle

The Unusual State-Dependent Affinity of P2X3 Receptors Can Be Explained by an Allosteric Two-Open-State Model

R. Karoly, A. Mike, P. Illes and Z. Gerevich
Molecular Pharmacology January 1, 2008, 73 (1) 224-234; DOI: https://doi.org/10.1124/mol.107.038901

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Research ArticleArticle

The Unusual State-Dependent Affinity of P2X3 Receptors Can Be Explained by an Allosteric Two-Open-State Model

R. Karoly, A. Mike, P. Illes and Z. Gerevich
Molecular Pharmacology January 1, 2008, 73 (1) 224-234; DOI: https://doi.org/10.1124/mol.107.038901
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