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Molecular Pharmacology

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Research ArticleArticle

Contribution of Individual Subunits to the Multimeric P2X2 Receptor: Estimates based on Methanethiosulfonate Block at T336C

Ron Stoop, Sarah Thomas, François Rassendren, Eric Kawashima, Gary Buell, Annmarie Surprenant and R. Alan North
Molecular Pharmacology November 1999, 56 (5) 973-981; DOI: https://doi.org/10.1124/mol.56.5.973
Ron Stoop
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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Sarah Thomas
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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François Rassendren
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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Eric Kawashima
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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Gary Buell
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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Annmarie Surprenant
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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R. Alan North
Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, Switzerland
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Abstract

P2X receptors are membrane proteins that incorporate a cation-selective ion channel that can be opened by the binding of extracellular ATP. They associate as hetero- and homo-multimers of currently unknown stoichiometry. In this study, we have used Xenopus laevis oocytes to express rat P2X2 receptor subunits, which carry a cysteine mutation at position 336. ATP-induced currents at this mutant receptor subunit were blocked by more than 90% when exposed to [2-(trimethylammonium) ethyl] methanethiosulfonate (MTSET), whereas currents from wild-type subunits were not affected. To compare mutant and wild-type channel expression, we introduced an epitope in their extracellular domains and found for both channels a similar linear relationship between antibody binding and currents induced by ATP. To study the contribution of the individual subunits to the block by MTSET, we coinjected different mixtures of wild-type and mutant-encoding mRNAs. We found that the inhibition by MTSET depended linearly on the proportion of mutant subunits, which was clearly contrary to the hypothesis that a single mutant subunit could act in a dominant fashion. Subsequent concatenation of wild-type and mutant-encoding cDNAs resulted in an inhibition by MTSET that also depended linearly on the number of mutant subunits and was independent of the position of the mutant subunit, as long as only two or three P2X2 subunits were joined. With four or six subunits joined, however, the inhibition by MTSET became strongly position-dependent. The present results show that a “per-subunit” channel block causes the blocking effects of MTSET and they suggest that not four but maximally three subunits actively participate in the channel formation.

Footnotes

    • Received February 17, 1999.
    • Accepted June 25, 1999.
  • Send reprint requests to: Dr. Ron Stoop, Institut de Biologie Cellulaire et de Morphologie, University of Lausanne, Rue du Bugnon 9, CH-1005 Lausanne, Switzerland. E-mail:ron.stoop{at}ibcm.unil.ch

  • ↵1 Present address: Institut de Biologie Cellulaire et de Morphologie, University of Lausanne, Lausanne, Switzerland.

  • ↵2 Present address: Department of Physiology and Pharmacology, University of Queensland, Brisbane, Australia.

  • ↵3 Present address: Institut de Génétique Humaine, Unité Propre de Recherche 1142, Montpellier, France.

  • ↵4 Present address: Ares Serono Pharmaceutical Research Institute, Geneva, Switzerland.

  • ↵5 Present address: Institute of Molecular Physiology, University of Sheffield, Sheffield, England, UK.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (5)
Molecular Pharmacology
Vol. 56, Issue 5
1 Nov 1999
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Research ArticleArticle

Contribution of Individual Subunits to the Multimeric P2X2 Receptor: Estimates based on Methanethiosulfonate Block at T336C

Ron Stoop, Sarah Thomas, François Rassendren, Eric Kawashima, Gary Buell, Annmarie Surprenant and R. Alan North
Molecular Pharmacology November 1, 1999, 56 (5) 973-981; DOI: https://doi.org/10.1124/mol.56.5.973

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Research ArticleArticle

Contribution of Individual Subunits to the Multimeric P2X2 Receptor: Estimates based on Methanethiosulfonate Block at T336C

Ron Stoop, Sarah Thomas, François Rassendren, Eric Kawashima, Gary Buell, Annmarie Surprenant and R. Alan North
Molecular Pharmacology November 1, 1999, 56 (5) 973-981; DOI: https://doi.org/10.1124/mol.56.5.973
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