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Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors

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Abstract

P2X1 receptors for ATP are ligand-gated cation channels, present on many excitable cells including vas deferens smooth muscle cells1,2,3,4,5. A substantial component of the contractile response of the vas deferens to sympathetic nerve stimulation, which propels sperm into the ejaculate, is mediated through P2X receptors1. Here we show that male fertility is reduced by ∼90% in mice with a targeted deletion of the P2X1 receptor gene. Male mice copulate normally—reduced fertility results from a reduction of sperm in the ejaculate and not from sperm dysfunction. Female mice and heterozygote mice are unaffected. In P2X1-receptor-deficient mice, contraction of the vas deferens to sympathetic nerve stimulation is reduced by up to 60% and responses to P2X receptor agonists are abolished. These results show that P2X1 receptors are essential for normal male reproductive function and suggest that the development of selective P2X1 receptor antagonists may provide an effective non-hormonal male contraceptive pill. Also, agents that potentiate the actions of ATP at P2X1 receptors may be useful in the treatment of male infertility.

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Figure 1: Generation of P2X1-receptor-deficient mice.
Figure 2: Immunohistochemical detection of P2X1 receptors and in vitro fertilization studies.
Figure 3: Response to purinergic agonists, nerve stimulation and noradrenaline of wild-type and P2X1-receptor-deficient mouse vas deferens.
Figure 4: Sympathetic nerve-mediated contraction of +/+ and -/- P2X1-receptor-deficient vas deferens.

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Acknowledgements

We thank L. Vulchanova and R. Elde for the P2X1 receptor antibody, B. Grubb and S. Giblett for help with the immunohistochemistry and C. d'Lacey for help with the confocal images. We also thank J. Luckett and S. Monkley for help at the bench and S. R. Nahorski for comments on the manuscript. This work was supported by the Medical Research Council and the Wellcome Trust.

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Author notes

  1. G. Buell

    Present address: Serono Pharmaceuticals, 14 chemin des Aulx, Plan-les-Ouates, 1228, Geneva, Switzerland

Authors and Affiliations

  1. Department of Cell Physiology & Pharmacology, Medical Sciences Building,

    K. Mulryan, D. P. Gitterman, C. J. Lewis, C. Vial & R. J. Evans

  2. Department of Medicine,

    B. J. Leckie

  3. Transgenic Unit, Biomedical Services,

    A. L. Cobb & J. E. Brown

  4. Department of Pathology and Centre for Mechanisms of Human Toxicity &,

    E. C. Conley

  5. Department of Biochemistry, University of Leicester, Leicester, LE1 9HN, UK

    C. A. Pritchard

  6. Glaxo-Wellcome Geneva Biomedical Research Institute, 14 chemin des Aulx, Plan-les-Ouates, Geneva, 1228, Switzerland

    G. Buell

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  1. K. Mulryan
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  2. D. P. Gitterman
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  11. R. J. Evans
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Correspondence to R. J. Evans.

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Mulryan, K., Gitterman, D., Lewis, C. et al. Reduced vas deferens contraction and male infertility in mice lacking P2X1 receptors. Nature 403, 86–89 (2000). https://doi.org/10.1038/47495

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  • DOI: https://doi.org/10.1038/47495

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