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Molecular Pharmacology

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Research ArticleArticle

Control of P2X3 Channel Function by Metabotropic P2Y2 UTP Receptors in Primary Sensory Neurons

Gary Mo, Jennifer C. Peleshok, Chang-Qing Cao, Alfredo Ribeiro-da-Silva and Philippe Séguéla
Molecular Pharmacology March 2013, 83 (3) 640-647; DOI: https://doi.org/10.1124/mol.112.082099
Gary Mo
Alan Edwards Research Centre on Pain (G.M., J.C.P., A.R.-d.-S., P.S.), Montreal, Quebec, Canada; Department of Bioscience (C.-Q.C.), AstraZeneca R&D Montreal, Ville-Saint-Laurent, Quebec, Canada; and Montreal Neurological Institute, Department of Neurology & Neurosurgery (G.M., P.S.), Department of Pharmacology (J.C.P., A.R.-d.-S.), and Department of Anatomy and Cell Biology (A.R.-d.-S.), McGill University, Montreal, Quebec, Canada
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Jennifer C. Peleshok
Alan Edwards Research Centre on Pain (G.M., J.C.P., A.R.-d.-S., P.S.), Montreal, Quebec, Canada; Department of Bioscience (C.-Q.C.), AstraZeneca R&D Montreal, Ville-Saint-Laurent, Quebec, Canada; and Montreal Neurological Institute, Department of Neurology & Neurosurgery (G.M., P.S.), Department of Pharmacology (J.C.P., A.R.-d.-S.), and Department of Anatomy and Cell Biology (A.R.-d.-S.), McGill University, Montreal, Quebec, Canada
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Chang-Qing Cao
Alan Edwards Research Centre on Pain (G.M., J.C.P., A.R.-d.-S., P.S.), Montreal, Quebec, Canada; Department of Bioscience (C.-Q.C.), AstraZeneca R&D Montreal, Ville-Saint-Laurent, Quebec, Canada; and Montreal Neurological Institute, Department of Neurology & Neurosurgery (G.M., P.S.), Department of Pharmacology (J.C.P., A.R.-d.-S.), and Department of Anatomy and Cell Biology (A.R.-d.-S.), McGill University, Montreal, Quebec, Canada
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Alfredo Ribeiro-da-Silva
Alan Edwards Research Centre on Pain (G.M., J.C.P., A.R.-d.-S., P.S.), Montreal, Quebec, Canada; Department of Bioscience (C.-Q.C.), AstraZeneca R&D Montreal, Ville-Saint-Laurent, Quebec, Canada; and Montreal Neurological Institute, Department of Neurology & Neurosurgery (G.M., P.S.), Department of Pharmacology (J.C.P., A.R.-d.-S.), and Department of Anatomy and Cell Biology (A.R.-d.-S.), McGill University, Montreal, Quebec, Canada
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Philippe Séguéla
Alan Edwards Research Centre on Pain (G.M., J.C.P., A.R.-d.-S., P.S.), Montreal, Quebec, Canada; Department of Bioscience (C.-Q.C.), AstraZeneca R&D Montreal, Ville-Saint-Laurent, Quebec, Canada; and Montreal Neurological Institute, Department of Neurology & Neurosurgery (G.M., P.S.), Department of Pharmacology (J.C.P., A.R.-d.-S.), and Department of Anatomy and Cell Biology (A.R.-d.-S.), McGill University, Montreal, Quebec, Canada
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Abstract

Purinergic signaling contributes significantly to pain mechanisms, and the nociceptor-specific P2X3 ATP receptor channel is considered a target in pain therapeutics. Recent findings suggesting the coexpression of metabotropic P2Y receptors with P2X3 implies that ATP release triggers the activation of both ionotropic and metabotropic purinoceptors, with strong potential for functional interaction. Modulation of native P2X3 function by P2Y receptor activation was investigated in rat dorsal root ganglia (DRG) neurons using whole cell patch-clamp recordings. Application of the selective P2Y receptor agonist UTP decreased peak amplitudes of α,β-meATP-evoked homomeric P2X3-mediated currents, but had no effect on heteromeric P2X2/3-mediated currents. Treatment with phospholipase C inhibitor U73122 significantly reversed P2X3 current inhibition induced by UTP-sensitive P2Y receptor activation. We previously reported the modulation of P2X receptors by phospholipids in DRG neurons and injection of exogenous phosphatidylinositol-4,5-bisphosphate (PIP2) fully reverses UTP-mediated regulation of P2X3 channel activity. Pharmacological as well as functional screening of P2Y receptor subtypes indicates the predominant involvement of P2Y2 receptor in P2X3 inhibition, and immunolocalization confirms a significant cellular coexpression of P2X3 and P2Y2 in rat DRG neurons. In summary, the function of P2X3 ATP receptor can be inhibited by P2Y2-mediated depletion of PIP2. We propose that expression of P2Y2 purinoceptor in nociceptive sensory neurons provides an homeostatic mechanism to prevent excessive ATP signaling through P2X3 receptor channels.

Footnotes

  • This work was supported by grants from the Canadian Institutes of Health Research (MOP-86527); National Science and Engineering Council (#203061); and by AstraZeneca R&D Montreal.

  • dx.doi.org/10.1124/mol.112.082099.

  • Received August 23, 2012.
  • Accepted December 18, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (3)
Molecular Pharmacology
Vol. 83, Issue 3
1 Mar 2013
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Research ArticleArticle

P2Y2-P2X3 Crosstalk in DRG Neurons

Gary Mo, Jennifer C. Peleshok, Chang-Qing Cao, Alfredo Ribeiro-da-Silva and Philippe Séguéla
Molecular Pharmacology March 1, 2013, 83 (3) 640-647; DOI: https://doi.org/10.1124/mol.112.082099

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Research ArticleArticle

P2Y2-P2X3 Crosstalk in DRG Neurons

Gary Mo, Jennifer C. Peleshok, Chang-Qing Cao, Alfredo Ribeiro-da-Silva and Philippe Séguéla
Molecular Pharmacology March 1, 2013, 83 (3) 640-647; DOI: https://doi.org/10.1124/mol.112.082099
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