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Molecular Pharmacology

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Research ArticleArticle

Evidence for Functional P2X4/P2X7 Heteromeric Receptors

Chang Guo, Marianela Masin, Omar S. Qureshi and Ruth D. Murrell-Lagnado
Molecular Pharmacology December 2007, 72 (6) 1447-1456; DOI: https://doi.org/10.1124/mol.107.035980
Chang Guo
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Marianela Masin
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Omar S. Qureshi
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Ruth D. Murrell-Lagnado
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Abstract

The cytolytic ionotropic ATP receptor P2X7 has several important roles in immune cell regulation, such as cytokine release, apoptosis, and microbial killing. Although P2X7 receptors are frequently coexpressed with another subtype of P2X receptor, P2X4, they are believed not to form heteromeric assemblies but to function only as homomers. Both receptors play a role in neuropathic pain; therefore, understanding how they coordinate the cellular response to ATP is important for the development of effective pain therapies. Here, we provide biochemical and electrophysiological evidence for an association between P2X4 and P2X7 that increases the diversity of receptor currents mediated via these two subtypes. The heterologously expressed receptors were coimmunoprecipitated from human embryonic kidney (HEK) 293 cells, and the endogenous P2X4 and P2X7 receptors were similarly coimmunoprecipitated from bone marrow-derived macrophages. In HEK293 cells, the fraction of P2X4 receptors biotinylated at the plasma membrane increased 2-fold in the presence of P2X7 although there was no change in overall expression. Coexpression of a dominant-negative P2X4 mutant (C353W) with P2X7, inhibited P2X7 receptor mediated currents by greater than 2-fold, whereas a nonfunctional but non–dominant-negative mutant (S341W) did not. Coexpression of P2X4S341W with P2X7 produced a current that was potentiated by ivermectin and inhibited by 2′,3′-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate (TNP-ATP), whereas expression of P2X7 alone produced a current that was insensitive to both of these compounds at the concentrations used. These results demonstrate a structural and functional interaction between P2X4 and P2X7, which suggests that they associate to form heteromeric receptors.

Footnotes

  • This work was supported by the Biotechnology and Biological Sciences Research Council.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

  • doi:10.1124/mol.107.035980.

  • ABBREVIATIONS: IL, interleukin; BzATP, 2′,3′-O-(benzoyl-4-benzoyl)-adenosine 5-triphosphate; NP-40, Nondiet P-40; EGFP, enhanced green fluorescent protein; ER, endoplasmic reticulum; FITC, fluorescein isothiocyanate; HA, hemagglutinin; HEK, human embryonic kidney; NRK, normal rat kidney; BMDM, bone marrow derived macrophage; PBS, phosphate-buffered saline; PAGE, polyacrylamide gel electrophoresis; TNP-ATP, 2′,3′-O-(2,4,6-trinitrophenyl) adenosine 5-triphosphate; BBG, Brilliant Blue G; EC, extracellular; wt, wild type; PFA, paraformaldehyde; DDM, n-dodecyl-b-d-maltoside; HRP, horseradish peroxidase; IVM, ivermectin; CHAPS, 3-[(3-cholamidopropyl)dimethylammonio]propanesulfonate; HBS, HEPES-buffered saline.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (6)
Molecular Pharmacology
Vol. 72, Issue 6
1 Dec 2007
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Research ArticleArticle

Evidence for Functional P2X4/P2X7 Heteromeric Receptors

Chang Guo, Marianela Masin, Omar S. Qureshi and Ruth D. Murrell-Lagnado
Molecular Pharmacology December 1, 2007, 72 (6) 1447-1456; DOI: https://doi.org/10.1124/mol.107.035980

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Research ArticleArticle

Evidence for Functional P2X4/P2X7 Heteromeric Receptors

Chang Guo, Marianela Masin, Omar S. Qureshi and Ruth D. Murrell-Lagnado
Molecular Pharmacology December 1, 2007, 72 (6) 1447-1456; DOI: https://doi.org/10.1124/mol.107.035980
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