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Proteomics to Identify Proteins Interacting with P2X2 Ligand-Gated Cation Channels
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Species Differences of P2X4 Receptor Modulators

Jessica Nagel1, Christiane Bous1, Aliaa Abdelrahman1

  • 1PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.

ACS Pharmacology & Translational Science
|May 15, 2025
PubMed

Insights

This study compares P2X4 receptors across nine species, finding significant potency differences for agonists and antagonists. These findings are crucial for selecting appropriate animal models in drug development for conditions like neuropathic pain.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • The P2X4 receptor, an ATP-gated ion channel, is a potential therapeutic target for neuropathic pain, neurodegenerative diseases, epilepsy, and cancer.
  • Animal models are essential for understanding receptor function in disease and for developing new drugs.

Purpose of the Study:

  • To systematically analyze and compare P2X4 receptors from nine species relevant to research: human, monkey, dog, guinea pig, pig, rabbit, rat, mouse, and zebrafish.
  • To evaluate species-specific responses to P2X4 receptor agonists and antagonists using calcium influx assays.

Main Methods:

  • Generated 1321N1 astrocytoma cell lines stably expressing P2X4 receptors from nine species via retroviral transfection.
  • Conducted calcium influx assays to assess the potency of diverse P2X4 receptor agonists and antagonists.
  • Analyzed species differences in receptor activity and drug responses.

Main Results:

  • Most agonists showed reduced potency in mice, rats, and zebrafish compared to the human P2X4 receptor.
  • ATP potency varied significantly across species, being more potent in monkey, rabbit, guinea pig, and pig P2X4 receptors than human, and least potent in zebrafish.
  • The antagonist PSB-OR-2020 demonstrated high potency and minimal species differences across all tested mammalian species.

Conclusions:

  • Significant species differences exist in P2X4 receptor pharmacology, impacting drug development and the choice of animal models.
  • 2-MeS-ATP is a suitable pan-species tool compound for studying P2X4 receptors, except in zebrafish.
  • The data provide valuable insights for future in vitro and in vivo studies, guiding the selection of appropriate models for P2X4 receptor research.

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