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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 Seguela
Molecular Pharmacology December 18, 2012, mol.112.082099; DOI: https://doi.org/10.1124/mol.112.082099
Gary Mo
1 McGill University;
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Jennifer C. Peleshok
1 McGill University;
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Chang-Qing Cao
2 AstraZeneca R&D Montreal;
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Alfredo Ribeiro-da-Silva
1 McGill University;
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Philippe Seguela
3 Montreal Neurological Institute
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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 evidence for co-expression of metabotropic P2Y receptors with P2X3 suggests 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 (PLC) 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 co-expression 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.

  • Purinergic
  • Ion channel regulation
  • Purinergic
  • Gq/11 family
  • Phospholipase C's
  • Lipid rafts/microdomains
  • Immunocytochemistry
  • Patch clamp methods
  • Received August 23, 2012.
  • Revision received December 18, 2012.
  • Accepted December 18, 2012.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 103 (2)
Molecular Pharmacology
Vol. 103, Issue 2
1 Feb 2023
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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 Seguela
Molecular Pharmacology December 18, 2012, mol.112.082099; DOI: https://doi.org/10.1124/mol.112.082099

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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 Seguela
Molecular Pharmacology December 18, 2012, mol.112.082099; DOI: https://doi.org/10.1124/mol.112.082099
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