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Evaluation of Plasma Membrane Calcium/Calmodulin-Dependent ATPase Isoform 4 as a Potential Target for Fertility Control

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Fertility Control

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 198))

Abstract

The array of contraceptives currently available is clearly inadequate and does not meet consumer demands since it is estimated that up to a quarter of all pregnancies worldwide are unintended. There is, therefore, an overwhelming global need to develop new effective, safe, ideally non-hormonal contraceptives for both male and female use. The contraceptive field, unlike other areas such as cancer, has a dearth of new targets. We have addressed this issue and propose that isoform 4 of the plasma membrane calcium ATPase is a potentially exciting novel target for fertility control. The plasma membrane calcium ATPase is a ubiquitously expressed calcium pump whose primary function in the majority of cells is to extrude calcium to the extracellular milieu. Two isoforms of this gene family, PMCA1 and PMCA4, are expressed in spermatozoa, with PMCA4 being the predominant isoform. Although this gene is ubiquitously expressed, its function is highly tissue-specific. Genetic deletion of PMCA4, in PMCA4 knockout mice, led to 100% infertility specifically in the male mutant mice due to a selective defect in sperm motility. It is important to note that the gene deletion did not affect normal mating characteristics in these mice. This phenotype was mimicked in wild-type sperm treated with the non-specific PMCA inhibitor 5-(and 6-) carboxyeosin diacetate succinimidyl ester; a proof-of-principle that inhibition of PMCA4 has potential importance in the control of fertility. This review outlines the potential for PMCA4 to be a novel target for fertility control by acting to inhibit sperm motility. It will outline the characteristics that make this target drugable and will describe methodologies to identify and validate novel inhibitors of this target.

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Acknowledgements

We would like to thank and acknowledge Florence Baudoin, Tamer Mohamed, Adam Pickard and Libby Oakden for their invaluable contributions to this project.

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Authors and Affiliations

  1. Cardiovascular Medicine, University of Manchester, Room 1.302 Stopford Building, Oxford Road, Manchester, UK

    Elizabeth J. Cartwright & Ludwig Neyses

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  1. Elizabeth J. Cartwright
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  2. Ludwig Neyses
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Correspondence to Elizabeth J. Cartwright .

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Editors and Affiliations

  1. , Women's Health Care Research, Bayer Schering Pharma AG, Berlin, 13342, Berlin, Germany

    Ursula-F. Habenicht

  2. ARC Centre of Excellence in, Biotechnology & Development, University of Newcastle, Callaghan, 2308, New South Wales, Australia

    R. John Aitken

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Cartwright, E.J., Neyses, L. (2010). Evaluation of Plasma Membrane Calcium/Calmodulin-Dependent ATPase Isoform 4 as a Potential Target for Fertility Control. In: Habenicht, UF., Aitken, R. (eds) Fertility Control. Handbook of Experimental Pharmacology, vol 198. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-02062-9_6

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