Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Sperm ion channels and transporters in male fertility and infertility

Nature Reviews Urology volume 18, pages 46–66 (2021)Cite this article

Subjects

Abstract

Mammalian sperm cells must respond to cues originating from along the female reproductive tract and from the layers of the egg in order to complete their fertilization journey. Dynamic regulation of ion signalling is, therefore, essential for sperm cells to adapt to their constantly changing environment. Over the past 15 years, direct electrophysiological recordings together with genetically modified mouse models and human genetics have confirmed the importance of ion channels, including the principal Ca2+-selective plasma membrane ion channel CatSper, for sperm activity. Sperm ion channels and membrane receptors are attractive targets for both the development of contraceptives and infertility treatment drugs. Furthermore, in this era of assisted reproductive technologies, understanding the signalling processes implicated in defective sperm function, particularly those arising from genetic abnormalities, is of the utmost importance not only for the development of infertility treatments but also to assess the overall health of a patient and his children. Future studies to improve reproductive health care and overall health care as a function of the ability to reproduce should include identification and analyses of gene variants that underlie human infertility and research into fertility-related molecules.

Key points

  • Mammalian sperm cells undergo intracellular alkalinization during their fertilization journey as they encounter a drastic extracellular pH change in the female reproductive tract.

  • During capacitation, the sperm membrane potential hyperpolarizes, primarily via KSper activation and K+ efflux.

  • Increases in intracellular Ca2+ are required for inducing hyperactivated motility and acrosome reaction, two key physiological events essential for fertilization.

  • CatSper, the multi-subunit Ca2+ channel, is the predominant Ca2+ entry pathway in sperm cells and organizes into linear Ca2+ signalling nanodomains along the flagella.

  • CatSper-mediated Ca2+ signalling is integrated into other sperm capacitation signalling pathways including phosphorylation cascades.

  • Improved understanding of spermatozoan ion channels and transporters will help elucidate the delicate and dynamic regulation of Ca2+ homeostasis in sperm motility and fertility.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Spermatozoan ion channels and membrane receptors.
Fig. 2: Quadrilinear CatSper Ca2+ signalling nanodomains in mammalian sperm.
Fig. 3: Capacitation-associated protein tyrosine phosphorylation.

Similar content being viewed by others

References

  1. Hille, B. Ion channels of excitable membranes (2001).

  2. Clapham, D. E. Calcium signaling. Cell 131, 1047–1058 (2007).

    CAS  PubMed  Google Scholar 

  3. Bagur, R. & Hajnóczky, G. Intracellular Ca2+ sensing: its role in calcium homeostasis and signaling. Mol. Cell 66, 780–788 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Bessen, M., Fay, R. B. & Witman, G. B. Calcium control of waveform in isolated flagellar axonemes of Chlamydomonas. J. Cell Biol. 86, 446–455 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Böhmer, M. et al. Ca2+ spikes in the flagellum control chemotactic behavior of sperm. EMBO J. 24, 2741–2752 (2005).

    PubMed  PubMed Central  Google Scholar 

  6. Wood, C. D., Nishigaki, T., Furuta, T., Baba, S. A. & Darszon, A. Real-time analysis of the role of Ca(2+) in flagellar movement and motility in single sea urchin sperm. J. Cell Biol. 169, 725–731 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Yanagimachi, R. et al. Chemical and physical guidance of fish spermatozoa into the egg through the micropyle. Biol. Reprod. 96, 780–799 (2017).

    PubMed  PubMed Central  Google Scholar 

  8. Suarez, S. S., Varosi, S. M. & Dai, X. Intracellular calcium increases with hyperactivation in intact, moving hamster sperm and oscillates with the flagellar beat cycle. Proc. Natl Acad. Sci. USA 90, 4660–4664 (1993).

    CAS  PubMed  Google Scholar 

  9. Smith, E. F. Regulation of flagellar dynein by calcium and a role for an axonemal calmodulin and calmodulin-dependent kinase. Mol. Biol. Cell 13, 3303–3313 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mizuno, K. et al. A novel neuronal calcium sensor family protein, calaxin, is a potential Ca(2+)-dependent regulator for the outer arm dynein of metazoan cilia and flagella. Biol. Cell 101, 91–103 (2009).

    CAS  PubMed  Google Scholar 

  11. Bannai, H., Yoshimura, M., Takahashi, K. & Shingyoji, C. Calcium regulation of microtubule sliding in reactivated sea urchin sperm flagella. J. Cell Sci. 113, 831–839 (2000).

    CAS  PubMed  Google Scholar 

  12. Tash, J. S. et al. Identification, characterization, and functional correlation of calmodulin-dependent protein phosphatase in sperm. J. Cell Biol. 106, 1625–1633 (1988).

    CAS  PubMed  Google Scholar 

  13. Kirichok, Y., Navarro, B. & Clapham, D. E. Whole-cell patch-clamp measurements of spermatozoa reveal an alkaline-activated Ca2+ channel. Nature 439, 737–740 (2006).

    CAS  PubMed  Google Scholar 

  14. Zeng, X. H., Navarro, B., Xia, X. M., Clapham, D. E. & Lingle, C. J. Simultaneous knockout of Slo3 and CatSper1 abolishes all alkalization- and voltage-activated current in mouse spermatozoa. J. Gen. Physiol. 142, 305–313 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ren, D. et al. A sperm ion channel required for sperm motility and male fertility. Nature 413, 603–609 (2001).

    CAS  PubMed  Google Scholar 

  16. Carlson, A. E. et al. CatSper1 required for evoked Ca2+ entry and control of flagellar function in sperm. Proc. Natl Acad. Sci. USA 100, 14864–14868 (2003).

    CAS  PubMed  Google Scholar 

  17. Quill, T. A. et al. Hyperactivated sperm motility driven by CatSper2 is required for fertilization. Proc. Natl Acad. Sci. USA 100, 14869–14874 (2003).

    CAS  PubMed  Google Scholar 

  18. Qi, H. et al. All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility. Proc. Natl Acad. Sci. USA 104, 1219–1223 (2007).

    CAS  PubMed  Google Scholar 

  19. Yanagimachi, R. The movement of golden hamster spermatozoa before and after capacitation. J. Reprod. Fertil. 23, 193–196 (1970).

    CAS  PubMed  Google Scholar 

  20. Suarez, S. S. & Ho, H. C. Hyperactivated motility in sperm. Reprod. Domest. Anim. 38, 119–124 (2003).

    CAS  PubMed  Google Scholar 

  21. Pacey, A. A., Davies, N., Warren, M. A., Barratt, C. L. & Cooke, I. D. Hyperactivation may assist human spermatozoa to detach from intimate association with the endosalpinx. Hum. Reprod. 10, 2603–2609 (1995).

    CAS  PubMed  Google Scholar 

  22. Ho, K., Wolff, C. A. & Suarez, S. S. CatSper-null mutant spermatozoa are unable to ascend beyond the oviductal reservoir. Reprod. Fertil. Dev. 21, 345–350 (2009).

    CAS  PubMed  Google Scholar 

  23. Miki, K. & Clapham, D. E. Rheotaxis guides mammalian sperm. Curr. Biol. 23, 443–452 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Coy, P., Garcia-Vazquez, F. A., Visconti, P. E. & Aviles, M. Roles of the oviduct in mammalian fertilization. Reproduction 144, 649–660 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Hunter, R. H. Components of oviduct physiology in eutherian mammals. Biol. Rev. Camb. Philos. Soc. 87, 244–255 (2012).

    CAS  PubMed  Google Scholar 

  26. Brenker, C. et al. The CatSper channel: a polymodal chemosensor in human sperm. EMBO J. 31, 1654–1665 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Lishko, P. V. et al. The control of male fertility by spermatozoan ion channels. Annu. Rev. Physiol. 74, 453–475 (2012).

    CAS  PubMed  Google Scholar 

  28. Miller, M. R., Mansell, S. A., Meyers, S. A. & Lishko, P. V. Flagellar ion channels of sperm: similarities and differences between species. Cell Calcium 58, 105–113 (2015).

    CAS  PubMed  Google Scholar 

  29. Chung, J. J. et al. CatSperζ regulates the structural continuity of sperm Ca(2+) signaling domains and is required for normal fertility. eLife 6, e23082 (2017).

    PubMed  PubMed Central  Google Scholar 

  30. Chung, J. J. et al. Structurally distinct Ca(2+) signaling domains of sperm flagella orchestrate tyrosine phosphorylation and motility. Cell 157, 808–822 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Hwang, J. Y. et al. Dual sensing of physiologic pH and calcium by EFCAB9 regulates sperm motility. Cell 177, 1480–1494.e19 (2019).

    CAS  PubMed  Google Scholar 

  32. Miller, M. R. et al. Asymmetrically positioned flagellar control units regulate human sperm rotation. Cell Rep. 24, 2606–2613 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Kerns, K., Zigo, M., Drobnis, E. Z., Sutovsky, M. & Sutovsky, P. Zinc ion flux during mammalian sperm capacitation. Nat. Commun. 9, 2061 (2018).

    PubMed  PubMed Central  Google Scholar 

  34. Matamoros-Volante, A. & Trevino, C. L. Capacitation-associated alkalization in human sperm is differentially controlled at the subcellular level. J. Cell Sci. 133, jcs238816 (2020).

    CAS  PubMed  Google Scholar 

  35. Matamoros-Volante, A. et al. Semi-automatized segmentation method using image-based flow cytometry to study sperm physiology: the case of capacitation-induced tyrosine phosphorylation. Mol. Hum. Reprod. 24, 64–73 (2018).

    CAS  PubMed  Google Scholar 

  36. Lin, J. & Nicastro, D. Asymmetric distribution and spatial switching of dynein activity generates ciliary motility. Science 360, eaar1968 (2018).

    PubMed  PubMed Central  Google Scholar 

  37. Zabeo, D., Croft, J. T. & Hoog, J. L. Axonemal doublet microtubules can split into two complete singlets in human sperm flagellum tips. FEBS Lett. 593, 892–902 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zabeo, D. et al. A lumenal interrupted helix in human sperm tail microtubules. Sci. Rep. 8, 2727 (2018).

    PubMed  PubMed Central  Google Scholar 

  39. Bernardino, R. L., Carrageta, D. F., Sousa, M., Alves, M. G. & Oliveira, P. F. pH and male fertility: making sense on pH homeodynamics throughout the male reproductive tract. Cell Mol. Life Sci. 76, 3783–3800 (2019).

    CAS  PubMed  Google Scholar 

  40. Levine, N. & Marsh, D. J. Micropuncture studies of the electrochemical aspects of fluid and electrolyte transport in individual seminiferous tubules, the epididymis and the vas deferens in rats. J. Physiol. 213, 557–570 (1971).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Wales, R. G., Wallace, J. C. & White, I. G. Composition of bull epididymal and testicular fluid. J. Reprod. Fertil. 12, 139–144 (1966).

    CAS  PubMed  Google Scholar 

  42. Liu, Y., Wang, D. K. & Chen, L. M. The physiology of bicarbonate transporters in mammalian reproduction. Biol. Reprod. 86, 99 (2012).

    PubMed  Google Scholar 

  43. Ng, K. Y. B., Mingels, R., Morgan, H., Macklon, N. & Cheong, Y. In vivo oxygen, temperature and pH dynamics in the female reproductive tract and their importance in human conception: a systematic review. Hum. Reprod. Update 24, 15–34 (2018).

    PubMed  Google Scholar 

  44. Breckenridge, M. A., Pederson, D. P. & Pommerenke, W. T. A pH study of human cervical secretions. Fertil. Steril. 1, 427–434 (1950).

    CAS  PubMed  Google Scholar 

  45. Fox, C. A., Meldrum, S. J. & Watson, B. W. Continuous measurement by radio-telemetry of vaginal pH during human coitus. J. Reprod. Fertil. 33, 69–75 (1973).

    CAS  PubMed  Google Scholar 

  46. Owen, D. H. & Katz, D. F. A review of the physical and chemical properties of human semen and the formulation of a semen simulant. J. Androl. 26, 459–469 (2005).

    CAS  PubMed  Google Scholar 

  47. Tampion, D. & Gibbons, R. A. Effect of pH on the swimming rate of bull spermatozoa. J. Reprod. Fertil. 5, 249–258 (1963).

    CAS  PubMed  Google Scholar 

  48. Moghissi, K. S., Dabich, D., Levine, J. & Neuhaus, O. W. Mechanism of sperm migration. Fertil. Steril. 15, 15–23 (1964).

    CAS  PubMed  Google Scholar 

  49. Orlowski, J. & Grinstein, S. Diversity of the mammalian sodium/proton exchanger SLC9 gene family. Pflug. Arch. 447, 549–565 (2004).

    CAS  Google Scholar 

  50. Garcia, M. A. & Meizel, S. Regulation of intracellular pH in capacitated human spermatozoa by a Na+/H+ exchanger. Mol. Reprod. Dev. 52, 189–195 (1999).

    CAS  PubMed  Google Scholar 

  51. Klanke, C. A. et al. Molecular cloning and physical and genetic mapping of a novel human Na+/H+ exchanger (NHE5/SLC9A5) to chromosome 16q22.1. Genomics 25, 615–622 (1995).

    CAS  PubMed  Google Scholar 

  52. Goyal, S., Vanden Heuvel, G. & Aronson, P. S. Renal expression of novel Na+/H+ exchanger isoform NHE8. Am. J. Physiol. Ren. Physiol. 284, F467–F473 (2003).

    CAS  Google Scholar 

  53. Wang, D., King, S. M., Quill, T. A., Doolittle, L. K. & Garbers, D. L. A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility. Nat. Cell Biol. 5, 1117–1122 (2003).

    CAS  PubMed  Google Scholar 

  54. Liu, T. et al. A novel testis-specific Na+/H+ exchanger is involved in sperm motility and fertility. Front. Biosci. 2, 566–581 (2010).

    Google Scholar 

  55. Chen, S. R. et al. Sodium-hydrogen exchanger NHA1 and NHA2 control sperm motility and male fertility. Cell Death Dis. 7, e2152 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Oberheide, K., Puchkov, D. & Jentsch, T. J. Loss of the Na(+)/H(+) exchanger NHE8 causes male infertility in mice by disrupting acrosome formation. J. Biol. Chem. 292, 10845–10854 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Wang, D. et al. A sperm-specific Na+/H+ exchanger (sNHE) is critical for expression and in vivo bicarbonate regulation of the soluble adenylyl cyclase (sAC). Proc. Natl Acad. Sci. USA 104, 9325–9330 (2007).

    CAS  PubMed  Google Scholar 

  58. Windler, F. et al. The solute carrier SLC9C1 is a Na(+)/H(+)-exchanger gated by an S4-type voltage-sensor and cyclic-nucleotide binding. Nat. Commun. 9, 2809 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lishko, P. V., Botchkina, I. L., Fedorenko, A. & Kirichok, Y. Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel. Cell 140, 327–337 (2010).

    CAS  PubMed  Google Scholar 

  60. Lee, S. Y., Letts, J. A. & Mackinnon, R. Dimeric subunit stoichiometry of the human voltage-dependent proton channel Hv1. Proc. Natl Acad. Sci. USA 105, 7692–7695 (2008).

    CAS  PubMed  Google Scholar 

  61. Tombola, F., Ulbrich, M. H. & Isacoff, E. Y. The voltage-gated proton channel Hv1 has two pores, each controlled by one voltage sensor. Neuron 58, 546–556 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ramsey, I. S. et al. An aqueous H+ permeation pathway in the voltage-gated proton channel Hv1. Nat. Struct. Mol. Biol. 17, 869–875 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Berger, T. K. et al. Post-translational cleavage of Hv1 in human sperm tunes pH- and voltage-dependent gating. J. Physiol. 595, 1533–1546 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Navarro, B., Kirichok, Y. & Clapham, D. E. KSper, a pH-sensitive K+ current that controls sperm membrane potential. Proc. Natl Acad. Sci. USA 104, 7688–7692 (2007).

    CAS  PubMed  Google Scholar 

  65. Brenker, C. et al. The Ca2+-activated K+ current of human sperm is mediated by Slo3. eLife 3, e01438 (2014).

    PubMed  PubMed Central  Google Scholar 

  66. Strunker, T. et al. The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 471, 382–386 (2011).

    PubMed  Google Scholar 

  67. Lishko, P. V., Botchkina, I. L. & Kirichok, Y. Progesterone activates the principal Ca2+ channel of human sperm. Nature 471, 387–391 (2011).

    CAS  PubMed  Google Scholar 

  68. Clausen, M. V., Hilbers, F. & Poulsen, H. The structure and function of the Na,K-ATPase isoforms in health and disease. Front. Physiol. 8, 371 (2017).

    PubMed  PubMed Central  Google Scholar 

  69. Huxley, A. F. & Stampfli, R. Direct determination of membrane resting potential and action potential in single myelinated nerve fibers. J. Physiol. 112, 476–495 (1951).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Santi, C. M. et al. The SLO3 sperm-specific potassium channel plays a vital role in male fertility. FEBS Lett. 584, 1041–1046 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Calzada, L. & Tellez, J. Defective function of membrane potential (psi) on sperm of infertile men. Arch. Androl. 38, 151–155 (1997).

    CAS  PubMed  Google Scholar 

  72. Brown, S. G. et al. Depolarization of sperm membrane potential is a common feature of men with subfertility and is associated with low fertilization rate at IVF. Hum. Reprod. 31, 1147–1157 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Baro Graf, C. et al. Membrane potential assessment by fluorimetry as a predictor tool of human sperm fertilizing capacity. Front. Cell Dev. Biol. 7, 383 (2019).

    PubMed  Google Scholar 

  74. Molina, L. C. P. et al. Membrane potential determined by flow cytometry predicts fertilizing ability of human sperm. Front. Cell Dev. Biol. 7, 387 (2019).

    PubMed  Google Scholar 

  75. Sanchez, G., Nguyen, A. N. T., Timmerberg, B., Tash, J. S. & Blanco, G. The Na,K-ATPase α4 isoform from humans has distinct enzymatic properties and is important for sperm motility. Mol. Hum. Reprod. 12, 565–576 (2006).

    CAS  PubMed  Google Scholar 

  76. Wagoner, K., Sanchez, G., Nguyen, A. N., Enders, G. C. & Blanco, G. Different expression and activity of the α1 and α4 isoforms of the Na,K-ATPase during rat male germ cell ontogeny. Reproduction 130, 627–641 (2005).

    CAS  PubMed  Google Scholar 

  77. Jimenez, T. et al. Increased expression of the Na,K-ATPase alpha4 isoform enhances sperm motility in transgenic mice. Biol. Reprod. 84, 153–161 (2011).

    CAS  PubMed  Google Scholar 

  78. McDermott, J., Sanchez, G., Nangia, A. K. & Blanco, G. Role of human Na,K-ATPase alpha 4 in sperm function, derived from studies in transgenic mice. Mol. Reprod. Dev. 82, 167–181 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Jimenez, T., Sanchez, G., Wertheimer, E. & Blanco, G. Activity of the Na,K-ATPase α4 isoform is important for membrane potential, intracellular Ca2+, and pH to maintain motility in rat spermatozoa. Reproduction 139, 835–845 (2010).

    CAS  PubMed  Google Scholar 

  80. Blanco, G., Melton, R. J., Sanchez, G. & Mercer, R. W. Functional characterization of a testes-specific α-subunit isoform of the sodium/potassium adenosinetriphosphatase. Biochemistry 38, 13661–13669 (1999).

    CAS  PubMed  Google Scholar 

  81. James, P. F. et al. Identification of a specific role for the Na,K-ATPase α2 isoform as a regulator of calcium in the heart. Mol. Cell 3, 555–563 (1999).

    CAS  PubMed  Google Scholar 

  82. Jimenez, T., McDermott, J. P., Sánchez, G. & Blanco, G. Na,K-ATPase α4 isoform is essential for sperm fertility. Proc. Natl Acad. Sci. USA 108, 644–649 (2011).

    CAS  PubMed  Google Scholar 

  83. Cooper, T. G. et al. Mouse models of infertility due to swollen spermatozoa. Mol. Cell Endocrinol. 216, 55–63 (2004).

    CAS  PubMed  Google Scholar 

  84. Zeng, X. H., Yang, C., Kim, S. T., Lingle, C. J. & Xia, X. M. Deletion of the Slo3 gene abolishes alkalization-activated K+ current in mouse spermatozoa. Proc. Natl Acad. Sci. USA 108, 5879–5884 (2011).

    CAS  PubMed  Google Scholar 

  85. Yang, C., Zeng, X. H., Zhou, Y., Xia, X. M. & Lingle, C. J. LRRC52 (leucine-rich-repeat-containing protein 52), a testis-specific auxiliary subunit of the alkalization-activated Slo3 channel. Proc. Natl Acad. Sci. USA 108, 19419–19424 (2011).

    CAS  PubMed  Google Scholar 

  86. Zeng, X. H., Yang, C., Xia, X. M., Liu, M. & Lingle, C. J. SLO3 auxiliary subunit LRRC52 controls gating of sperm KSPER currents and is critical for normal fertility. Proc. Natl Acad. Sci. USA 112, 2599–2604 (2015).

    CAS  PubMed  Google Scholar 

  87. Mansell, S. A., Publicover, S. J., Barratt, C. L. & Wilson, S. M. Patch clamp studies of human sperm under physiological ionic conditions reveal three functionally and pharmacologically distinct cation channels. Mol. Hum. Reprod. 20, 392–408 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Mannowetz, N., Naidoo, N. M., Choo, S. A., Smith, J. F. & Lishko, P. V. Slo1 is the principal potassium channel of human spermatozoa. eLife 2, e01009 (2013).

    PubMed  PubMed Central  Google Scholar 

  89. Geng, Y. et al. A genetic variant of the sperm-specific SLO3 K(+) channel has altered pH and Ca(2+) sensitivities. J. Biol. Chem. 292, 8978–8987 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Wijerathne, T. D., Kim, J., Yang, D. & Lee, K. P. Intracellular calcium-dependent regulation of the sperm-specific calcium-activated potassium channel, hSlo3, by the BKCa activator LDD175. Korean J. Physiol. Pharmacol. 21, 241–249 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Chavez, J. C. et al. SLO3 K+ channels control calcium entry through CATSPER channels in sperm. J. Biol. Chem. 289, 32266–32275 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Brown, S. G., Publicover, S. J., Barratt, C. L. R. & Martins da Silva, S. J. Human sperm ion channel (dys)function: implications for fertilization. Hum. Reprod. Update 25, 758–776 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Lievano, A. et al. T-type Ca2+ channels and α1E expression in spermatogenic cells, and their possible relevance to the sperm acrosome reaction. FEBS Lett. 388, 150–154 (1996).

    CAS  PubMed  Google Scholar 

  94. Xia, J. & Ren, D. Egg coat proteins activate calcium entry into mouse sperm via CATSPER channels. Biol. Reprod. 80, 1092–1098 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Jin, J. et al. Catsper3 and Catsper4 are essential for sperm hyperactivated motility and male fertility in the mouse. Biol. Reprod. 77, 37–44 (2007).

    CAS  PubMed  Google Scholar 

  96. Liu, J., Xia, J., Cho, K. H., Clapham, D. E. & Ren, D. CatSperbeta, a novel transmembrane protein in the CatSper channel complex. J. Biol. Chem. 282, 18945–18952 (2007).

    CAS  PubMed  Google Scholar 

  97. Wang, H., Liu, J., Cho, K. H. & Ren, D. A novel, single, transmembrane protein CATSPERG is associated with CATSPER1 channel protein. Biol. Reprod. 81, 539–544 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Chung, J. J., Navarro, B., Krapivinsky, G., Krapivinsky, L. & Clapham, D. E. A novel gene required for male fertility and functional CATSPER channel formation in spermatozoa. Nat. Commun. 2, 153 (2011).

    PubMed  PubMed Central  Google Scholar 

  99. Carlson, A. E. et al. Identical phenotypes of CatSper1 and CatSper2 null sperm. J. Biol. Chem. 280, 32238–32244 (2005).

    CAS  PubMed  Google Scholar 

  100. Avenarius, M. R. et al. Human male infertility caused by mutations in the CATSPER1 channel protein. Am. J. Hum. Genet. 84, 505–510 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Hildebrand, M. S. et al. Genetic male infertility and mutation of CATSPER ion channels. Eur. J. Hum. Genet. 18, 1178–1184 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Smith, J. F. et al. Disruption of the principal, progesterone-activated sperm Ca2+ channel in a CatSper2-deficient infertile patient. Proc. Natl Acad. Sci. USA 110, 6823–6828 (2013).

    CAS  PubMed  Google Scholar 

  103. Schiffer, C. et al. Rotational motion and rheotaxis of human sperm do not require functional CatSper channels and transmembrane Ca(2+) signaling. EMBO J. 39, e102363 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Luo, T. et al. A novel copy number variation in CATSPER2 causes idiopathic male infertility with normal semen parameters. Hum. Reprod. 34, 414–423 (2019).

    PubMed  Google Scholar 

  105. Sinha, A., Singh, V., Singh, S. & Yadav, S. Proteomic analyses reveal lower expression of TEX40 and ATP6V0A2 proteins related to calcium ion entry and acrosomal acidification in asthenozoospermic males. Life Sci. 218, 81–88 (2019).

    CAS  PubMed  Google Scholar 

  106. Brown, S. G. et al. Homozygous in-frame deletion in CATSPERE in a man producing spermatozoa with loss of CatSper function and compromised fertilizing capacity. Hum. Reprod. 33, 1812–1816 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Williams, H. L. et al. Specific loss of CatSper function is sufficient to compromise fertilizing capacity of human spermatozoa. Hum. Reprod. 30, 2737–2746 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. San Agustin, J. T., Pazour, G. J. & Witman, G. B. Intraflagellar transport is essential for mammalian spermiogenesis but is absent in mature sperm. Mol. Biol. Cell 26, 4358–4372 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang, Y. et al. Intraflagellar transporter protein (IFT27), an IFT25 binding partner, is essential for male fertility and spermiogenesis in mice. Dev. Biol. 432, 125–139 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Liu, H. et al. IFT25, an intraflagellar transporter protein dispensable for ciliogenesis in somatic cells, is essential for sperm flagella formation. Biol. Reprod. 96, 993–1006 (2017).

    PubMed  PubMed Central  Google Scholar 

  111. Zhang, Y. et al. Sensorineural deafness and male infertility: a contiguous gene deletion syndrome. J. Med. Genet. 44, 233–240 (2007).

    CAS  PubMed  Google Scholar 

  112. Avidan, N. et al. CATSPER2, a human autosomal nonsyndromic male infertility gene. Eur. J. Hum. Genet. 11, 497–502 (2003).

    CAS  PubMed  Google Scholar 

  113. Sumigama, S. et al. Progesterone accelerates the completion of sperm capacitation and activates CatSper channel in spermatozoa from the rhesus macaque. Biol. Reprod. 93, 130 (2015).

    PubMed  PubMed Central  Google Scholar 

  114. Miller, M. R. et al. Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone. Science 352, 555–559 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Mannowetz, N., Miller, M. R. & Lishko, P. V. Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids. Proc. Natl Acad. Sci. USA 114, 5743–5748 (2017).

    CAS  PubMed  Google Scholar 

  116. Brenker, C. et al. Action of steroids and plant triterpenoids on CatSper Ca(2+) channels in human sperm. Proc. Natl Acad. Sci. USA 115, E344–E346 (2018).

    CAS  PubMed  Google Scholar 

  117. Mannowetz, N., Mundt, N. & Lishko, P. V. Reply to Brenker et al.: The plant triterpenoid pristimerin inhibits calcium influx into human spermatozoa via CatSper. Proc. Natl Acad. Sci. USA 115, E347–E348 (2018).

    CAS  PubMed  Google Scholar 

  118. Diao, R. et al. CCR6 is required for ligand-induced CatSper activation in human sperm. Oncotarget 8, 91445–91458 (2017).

    PubMed  PubMed Central  Google Scholar 

  119. Schiffer, C. et al. Direct action of endocrine disrupting chemicals on human sperm. EMBO Rep. 15, 758–765 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Tavares, R. S. et al. p,p′-DDE activates CatSper and compromises human sperm function at environmentally relevant concentrations. Hum. Reprod. 28, 3167–3177 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Zou, Q. X. et al. Diethylstilbestrol activates CatSper and disturbs progesterone actions in human spermatozoa. Hum. Reprod. 32, 290–298 (2017).

    CAS  PubMed  Google Scholar 

  122. Bailey, J. L. Factors regulating sperm capacitation. Syst. Biol. Reprod. Med. 56, 334–348 (2010).

    CAS  PubMed  Google Scholar 

  123. Jaiswal, B. S. & Conti, M. Calcium regulation of the soluble adenylyl cyclase expressed in mammalian spermatozoa. Proc. Natl Acad. Sci. USA 100, 10676–10681 (2003).

    CAS  PubMed  Google Scholar 

  124. Xie, F. et al. Soluble adenylyl cyclase (sAC) is indispensable for sperm function and fertilization. Dev. Biol. 296, 353–362 (2006).

    CAS  PubMed  Google Scholar 

  125. Nolan, M. A. et al. Sperm-specific protein kinase A catalytic subunit Cα2 orchestrates cAMP signaling for male fertility. Proc. Natl Acad. Sci. USA 101, 13483–13488 (2004).

    CAS  PubMed  Google Scholar 

  126. Xia, J., Reigada, D., Mitchell, C. H. & Ren, D. CATSPER channel-mediated Ca2+ entry into mouse sperm triggers a tail-to-head propagation. Biol. Reprod. 77, 551–559 (2007).

    CAS  PubMed  Google Scholar 

  127. Kobori, H., Miyazaki, S. & Kuwabara, Y. Characterization of intracellular Ca(2+) increase in response to progesterone and cyclic nucleotides in mouse spermatozoa. Biol. Reprod. 63, 113–120 (2000).

    CAS  PubMed  Google Scholar 

  128. Carlson, A. E., Hille, B. & Babcock, D. F. External Ca2+ acts upstream of adenylyl cyclase SACY in the bicarbonate signaled activation of sperm motility. Dev. Biol. 312, 183–192 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Wang, T. et al. The Ca(2+) channel CatSper is not activated by cAMP/PKA signaling but directly affected by chemicals used to probe the action of cAMP and PKA. J. Biol. Chem. 295, 13181–13193 (2020).

    CAS  PubMed  Google Scholar 

  130. Orta, G. et al. CatSper channels are regulated by protein kinase A. J. Biol. Chem. 293, 16830–16841 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Gadella, B. M. & Harrison, R. A. The capacitating agent bicarbonate induces protein kinase A-dependent changes in phospholipid transbilayer behavior in the sperm plasma membrane. Development 127, 2407–2420 (2000).

    CAS  PubMed  Google Scholar 

  132. Visconti, P. E. et al. Cholesterol efflux-mediated signal transduction in mammalian sperm: cholesterol release signals an increase in protein tyrosine phosphorylation during mouse sperm capacitation. Dev. Biol. 214, 429–443 (1999).

    CAS  PubMed  Google Scholar 

  133. Xia, J. & Ren, D. The BSA-induced Ca2+ influx during sperm capacitation is CATSPER channel-dependent. Reprod. Biol. Endocrinol. 7, 119 (2009).

    PubMed  PubMed Central  Google Scholar 

  134. Visconti, P. E. et al. Cholesterol efflux-mediated signal transduction in mammalian sperm: β-cyclodextrins initiate transmembrane signaling leading to an increase in protein tyrosine phosphorylation and capacitation. J. Biol. Chem. 274, 3235–3242 (1999).

    CAS  PubMed  Google Scholar 

  135. Osheroff, J. E. et al. Regulation of human sperm capacitation by a cholesterol efflux-stimulated signal transduction pathway leading to protein kinase A-mediated up-regulation of protein tyrosine phosphorylation. Mol. Hum. Reprod. 5, 1017–1026 (1999).

    CAS  PubMed  Google Scholar 

  136. Harrison, R. A. Rapid PKA-catalysed phosphorylation of boar sperm proteins induced by the capacitating agent bicarbonate. Mol. Reprod. Dev. 67, 337–352 (2004).

    CAS  PubMed  Google Scholar 

  137. Battistone, M. A. et al. Functional human sperm capacitation requires both bicarbonate-dependent PKA activation and down-regulation of Ser/Thr phosphatases by Src family kinases. Mol. Hum. Reprod. 19, 570–580 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Wennemuth, G. et al. Bicarbonate actions on flagellar and Ca2+-channel responses: initial events in sperm activation. Development 130, 1317–1326 (2003).

    CAS  PubMed  Google Scholar 

  139. Visconti, P. E. et al. Capacitation of mouse spermatozoa. I. Correlation between the capacitation state and protein-tyrosine phosphorylation. Development 121, 1129–1137 (1995).

    CAS  PubMed  Google Scholar 

  140. Salicioni, A. M. et al. Signalling pathways involved in sperm capacitation. Soc. Reprod. Fertil. Suppl. 65, 245–259 (2007).

    CAS  PubMed  Google Scholar 

  141. Visconti, P. E. et al. Capacitation of mouse spermatozoa. II. Protein-tyrosine phosphorylation and capacitation are regulated by a cAMP-dependent pathway. Development 121, 1139–1150 (1995).

    CAS  PubMed  Google Scholar 

  142. Alvau, A. et al. The tyrosine kinase FER is responsible for the capacitation-associated increase in tyrosine phosphorylation in murine sperm. Development 143, 2325–2333 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Craig, A. W. B., Zirngibl, R., Williams, K., Cole, L. A. & Greer, P. A. Mice devoid of Fer protein-tyrosine kinase activity are viable and fertile but display reduced cortactin phosphorylation. Mol. Cell. Biol. 21, 603–613 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Tateno, H. et al. Ca2+ ionophore A23187 can make mouse spermatozoa capable of fertilizing in vitro without activation of cAMP-dependent phosphorylation pathways. Proc. Natl Acad. Sci. USA 110, 18543–18548 (2013).

    CAS  PubMed  Google Scholar 

  145. Navarrete, F. A. et al. Transient exposure to calcium ionophore enables in vitro fertilization in sterile mouse models. Sci. Rep. 6, 33589 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Miyata, H. et al. Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive. Science 350, 442–445 (2015).

    CAS  PubMed  Google Scholar 

  147. Mundt, N., Spehr, M. & Lishko, P. V. TRPV4 is the temperature-sensitive ion channel of human sperm. eLife 7, e35853 (2018).

    PubMed  PubMed Central  Google Scholar 

  148. Bahat, A. et al. Thermotaxis of mammalian sperm cells: a potential navigation mechanism in the female genital tract. Nat. Med. 9, 149 (2003).

    CAS  PubMed  Google Scholar 

  149. Boryshpolets, S., Pérez-Cerezales, S. & Eisenbach, M. Behavioral mechanism of human sperm in thermotaxis: a role for hyperactivation. Hum. Reprod. 30, 884–892 (2015).

    PubMed  Google Scholar 

  150. Aitken, R. J. & Nixon, B. Sperm capacitation: a distant landscape glimpsed but unexplored. Mol. Hum. Reprod. 19, 785–793 (2013).

    CAS  PubMed  Google Scholar 

  151. Hamano, K., Kawanishi, T., Mizuno, A., Suzuki, M. & Takagi, Y. Involvement of transient receptor potential vanilloid (TRPV) 4 in mouse sperm thermotaxis. J. Reprod. Dev. 62, 415–422 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Kumar, A. et al. TRPV4 is endogenously expressed in vertebrate spermatozoa and regulates intracellular calcium in human sperm. Biochem. Biophys. Res. Commun. 473, 781–788 (2016).

    CAS  PubMed  Google Scholar 

  153. Bjorkgren, I. & Lishko, P. V. Purinergic signaling in testes revealed. J. Gen. Physiol. 148, 207–211 (2016).

    PubMed  PubMed Central  Google Scholar 

  154. Navarro, B., Miki, K. & Clapham, D. E. ATP-activated P2X2 current in mouse spermatozoa. Proc. Natl Acad. Sci. USA 108, 14342–14347 (2011).

    CAS  PubMed  Google Scholar 

  155. King, B. F., Wildman, S. S., Ziganshina, L. E., Pintor, J. & Burnstock, G. Effects of extracellular pH on agonism and antagonism at a recombinant P2X2 receptor. Br. J. Pharmacol. 121, 1445–1453 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Wildman, S. S., King, B. F. & Burnstock, G. Zn2+ modulation of ATP-responses at recombinant P2X2 receptors and its dependence on extracellular pH. Br. J. Pharmacol. 123, 1214–1220 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. Catterall, W. A., Goldin, A. L. & Waxman, S. G. International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57, 397–409 (2005).

    CAS  PubMed  Google Scholar 

  158. Westenbroek, R. E. & Babcock, D. F. Discrete regional distributions suggest diverse functional roles of calcium channel α1 subunits in sperm. Dev. Biol. 207, 457–469 (1999).

    CAS  PubMed  Google Scholar 

  159. Wennemuth, G., Westenbroek, R. E., Xu, T., Hille, B. & Babcock, D. F. CaV2.2 and CaV2.3 (N- and R-type) Ca2+ channels in depolarization-evoked entry of Ca2+ into mouse sperm. J. Biol. Chem. 275, 21210–21217 (2000).

    CAS  PubMed  Google Scholar 

  160. Sakata, Y. et al. Ca(v)2.3 (α1E) Ca2+ channel participates in the control of sperm function. FEBS Lett. 516, 229–233 (2002).

    CAS  PubMed  Google Scholar 

  161. Cohen, R. et al. Lipid modulation of calcium flux through CaV2.3 regulates acrosome exocytosis and fertilization. Dev. Cell 28, 310–321 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Kirichok, Y. & Lishko, P. V. Rediscovering sperm ion channels with the patch-clamp technique. Mol. Hum. Reprod. 17, 478–499 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Shen, P. S. et al. The structure of the polycystic kidney disease channel PKD2 in lipid nanodiscs. Cell 167, 763–773.e11 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Cordido, A., Besada-Cerecedo, L. & Garcia-Gonzalez, M. A. The genetic and cellular basis of autosomal dominant polycystic kidney disease–a primer for clinicians. Front. Pediatr. 5, 279 (2017).

    PubMed  PubMed Central  Google Scholar 

  165. Yoder, B. K., Hou, X. & Guay-Woodford, L. M. The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J. Am. Soc. Nephrol. 13, 2508–2516 (2002).

    CAS  PubMed  Google Scholar 

  166. Su, Q. et al. Structure of the human PKD1-PKD2 complex. Science 361, eaat9819 (2018).

    PubMed  Google Scholar 

  167. Kierszenbaum, A. L. Polycystins: what polycystic kidney disease tells us about sperm. Mol. Reprod. Dev. 67, 385–388 (2004).

    CAS  PubMed  Google Scholar 

  168. Vora, N., Perrone, R. & Bianchi, D. W. Reproductive issues for adults with autosomal dominant polycystic kidney disease. Am. J. Kidney Dis. 51, 307–318 (2008).

    PubMed  Google Scholar 

  169. Li Vecchi, M., Cianfrone, P., Damiano, R. & Fuiano, G. Infertility in adults with polycystic kidney disease. Nephrol. Dial. Transpl. 18, 190–191 (2003).

    Google Scholar 

  170. Okada, H. et al. Assisted reproduction for infertile patients with 9+0 immotile spermatozoa associated with autosomal dominant polycystic kidney disease. Hum. Reprod. 14, 110–113 (1999).

    CAS  PubMed  Google Scholar 

  171. Sutton, K. A., Jungnickel, M. K. & Florman, H. M. A polycystin-1 controls postcopulatory reproductive selection in mice. Proc. Natl Acad. Sci. USA 105, 8661–8666 (2008).

    CAS  PubMed  Google Scholar 

  172. Hughes, J., Ward, C. J., Aspinwall, R., Butler, R. & Harris, P. C. Identification of a human homologue of the sea urchin receptor for egg jelly: a polycystic kidney disease-like protein. Hum. Mol. Genet. 8, 543–549 (1999).

    CAS  PubMed  Google Scholar 

  173. Butscheid, Y. et al. Polycystic kidney disease and receptor for egg jelly is a plasma membrane protein of mouse sperm head. Mol. Reprod. Dev. 73, 350–360 (2006).

    CAS  PubMed  Google Scholar 

  174. Linsdell, P. et al. Permeability of wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride channels to polyatomic anions. J. Gen. Physiol. 110, 355–364 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Illek, B., Yankaskas, J. R. & Machen, T. E. cAMP and genistein stimulate HCO3- conductance through CFTR in human airway epithelia. Am. J. Physiol. 272, L752–L761 (1997).

    CAS  PubMed  Google Scholar 

  176. Chen, H., Ruan, Y. C., Xu, W. M., Chen, J. & Chan, H. C. Regulation of male fertility by CFTR and implications in male infertility. Hum. Reprod. Update 18, 703–713 (2012).

    CAS  PubMed  Google Scholar 

  177. van der Ven, K., Messer, L., van der Ven, H., Jeyendran, R. S. & Ober, C. Cystic fibrosis mutation screening in healthy men with reduced sperm quality. Hum. Reprod. 11, 513–517 (1996).

    PubMed  Google Scholar 

  178. Xu, W. M. et al. Cystic fibrosis transmembrane conductance regulator is vital to sperm fertilizing capacity and male fertility. Proc. Natl Acad. Sci. USA 104, 9816–9821 (2007).

    CAS  PubMed  Google Scholar 

  179. Snouwaert, J. N. et al. An animal model for cystic fibrosis made by gene targeting. Science 257, 1083–1088 (1992).

    CAS  PubMed  Google Scholar 

  180. Li, C. Y. et al. CFTR is essential for sperm fertilizing capacity and is correlated with sperm quality in humans. Hum. Reprod. 25, 317–327 (2010).

    CAS  PubMed  Google Scholar 

  181. Hernandez-Gonzalez, E. O. et al. Involvement of cystic fibrosis transmembrane conductance regulator in mouse sperm capacitation. J. Biol. Chem. 282, 24397–24406 (2007).

    CAS  PubMed  Google Scholar 

  182. Chen, W. Y. et al. Cl− is required for HCO3− entry necessary for sperm capacitation in guinea pig: involvement of a Cl−/HCO3− exchanger (SLC26A3) and CFTR. Biol. Reprod. 80, 115–123 (2009).

    CAS  PubMed  Google Scholar 

  183. Chavez, J. C. et al. Participation of the Cl−/HCO3− exchangers SLC26A3 and SLC26A6, the Cl− channel CFTR, and the regulatory factor SLC9A3R1 in mouse sperm capacitation. Biol. Reprod. 86, 1–14 (2012).

    PubMed  Google Scholar 

  184. Hoglund, P. et al. Disruption of the SLC26A3-mediated anion transport is associated with male subfertility. Fertil. Steril. 85, 232–235 (2006).

    CAS  PubMed  Google Scholar 

  185. Schweinfest, C. W. et al. slc26a3 (dra)-deficient mice display chloride-losing diarrhea, enhanced colonic proliferation, and distinct up-regulation of ion transporters in the colon. J. Biol. Chem. 281, 37962–37971 (2006).

    CAS  PubMed  Google Scholar 

  186. Wang, Y. Y. et al. Loss of SLC9A3 decreases CFTR protein and causes obstructed azoospermia in mice. PLoS Genet. 13, e1006715 (2017).

    PubMed  PubMed Central  Google Scholar 

  187. Figueiras-Fierro, D. et al. Electrophysiological evidence for the presence of cystic fibrosis transmembrane conductance regulator (CFTR) in mouse sperm. J. Cell Physiol. 228, 590–601 (2013).

    CAS  PubMed  Google Scholar 

  188. Rode, B. et al. The testis anion transporter TAT1 (SLC26A8) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel: a potential role during sperm capacitation. Hum. Mol. Genet. 21, 1287–1298 (2012).

    CAS  PubMed  Google Scholar 

  189. Strehler, E. E. & Zacharias, D. A. Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps. Physiol. Rev. 81, 21–50 (2001).

    CAS  PubMed  Google Scholar 

  190. Keeton, T. P., Burk, S. E. & Shull, G. E. Alternative splicing of exons encoding the calmodulin-binding domains and C termini of plasma membrane Ca(2+)-ATPase isoforms 1, 2, 3, and 4. J. Biol. Chem. 268, 2740–2748 (1993).

    CAS  PubMed  Google Scholar 

  191. Okunade, G. W. et al. Targeted ablation of plasma membrane Ca2+-ATPase (PMCA) 1 and 4 indicates a major housekeeping function for PMCA1 and a critical role in hyperactivated sperm motility and male fertility for PMCA4. J. Biol. Chem. 279, 33742–33750 (2004).

    CAS  PubMed  Google Scholar 

  192. Schuh, K. et al. Plasma membrane Ca2+ ATPase 4 is required for sperm motility and male fertility. J. Biol. Chem. 279, 28220–28226 (2004).

    CAS  PubMed  Google Scholar 

  193. Prasad, V., Okunade, G. W., Miller, M. L. & Shull, G. E. Phenotypes of SERCA and PMCA knockout mice. Biochem. Biophys. Res. Commun. 322, 1192–1203 (2004).

    CAS  PubMed  Google Scholar 

  194. Yamazaki, D. et al. Basolateral Mg2+ extrusion via CNNM4 mediates transcellular Mg2+ transport across epithelia: a mouse model. PLoS Genet. 9, e1003983 (2013).

    PubMed  PubMed Central  Google Scholar 

  195. Yamazaki, D. et al. The Mg2+ transporter CNNM4 regulates sperm Ca2+ homeostasis and is essential for reproduction. J. Cell Sci. 129, 1940–1949 (2016).

    CAS  PubMed  Google Scholar 

  196. Yamazaki, D., Funato, Y., Miyata, H., Ikawa, M. & Miki, H. Complementary role of CNNM2 in sperm motility and Ca(2+) influx during capacitation. Biochem. Biophys. Res. Commun. 474, 441–446 (2016).

    CAS  PubMed  Google Scholar 

  197. Long, J. E., Lee, M. S. & Blithe, D. L. Male contraceptive development: update on novel hormonal and nonhormonal methods. Clin. Chem. 65, 153–160 (2019).

    CAS  PubMed  Google Scholar 

  198. Hauser, A. S., Attwood, M. M., Rask-Andersen, M., Schioth, H. B. & Gloriam, D. E. Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov. 16, 829–842 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Garcia, M. L. & Kaczorowski, G. J. Ion channels find a pathway for therapeutic success. Proc. Natl Acad. Sci. USA 113, 5472–5474 (2016).

    CAS  PubMed  Google Scholar 

  200. McManus, O. B. HTS assays for developing the molecular pharmacology of ion channels. Curr. Opin. Pharmacol. 15, 91–96 (2014).

    CAS  PubMed  Google Scholar 

  201. Rennhack, A. et al. A novel cross-species inhibitor to study the function of CatSper Ca(2+) channels in sperm. Br. J. Pharmacol. 175, 3144–3161 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Schaefer, M., Habenicht, U. F., Brautigam, M. & Gudermann, T. Steroidal sigma receptor ligands affect signaling pathways in human spermatozoa. Biol. Reprod. 63, 57–63 (2000).

    CAS  PubMed  Google Scholar 

  203. Gruber, F. S., Johnston, Z. C., Barratt, C. L. & Andrews, P. D. A phenotypic screening platform utilising human spermatozoa identifies compounds with contraceptive activity. eLife 9, e51739 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Janes, J. et al. The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Proc. Natl Acad. Sci. USA 115, 10750–10755 (2018).

    CAS  PubMed  Google Scholar 

  205. Choy, J. T. & Eisenberg, M. L. Male infertility as a window to health. Fertil. Steril. 110, 810–814 (2018).

    PubMed  Google Scholar 

  206. De Jonge, C. & Barratt, C. L. R. The present crisis in male reproductive health: an urgent need for a political, social, and research roadmap. Andrology 7, 762–768 (2019).

    PubMed  Google Scholar 

  207. Sermondade, N. et al. BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis. Hum. Reprod. Update 19, 221–231 (2013).

    CAS  PubMed  Google Scholar 

  208. Li, Y., Lin, H., Li, Y. & Cao, J. Association between socio-psycho-behavioral factors and male semen quality: systematic review and meta-analyses. Fertil. Steril. 95, 116–123 (2011).

    PubMed  Google Scholar 

  209. Trottmann, M. et al. Semen quality in men with malignant diseases before and after therapy and the role of cryopreservation. Eur. Urol. 52, 355–367 (2007).

    PubMed  Google Scholar 

  210. Jacobsen, R. et al. Risk of testicular cancer in men with abnormal semen characteristics: cohort study. BMJ 321, 789–792 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Walsh, T. J., Croughan, M. S., Schembri, M., Chan, J. M. & Turek, P. J. Increased risk of testicular germ cell cancer among infertile men. Arch. Intern. Med. 169, 351–356 (2009).

    PubMed  PubMed Central  Google Scholar 

  212. Breuss, M. W. et al. Autism risk in offspring can be assessed through quantification of male sperm mosaicism. Nat. Med. 26, 143–150 (2020).

    CAS  PubMed  Google Scholar 

  213. Leung, A. K., Henry, M. A. & Mehta, A. Gaps in male infertility health services research. Transl. Androl. Urol. 7, S303–S309 (2018).

    PubMed  PubMed Central  Google Scholar 

  214. Yu, J., Chen, Z., Ni, Y. & Li, Z. CFTR mutations in men with congenital bilateral absence of the vas deferens (CBAVD): a systemic review and meta-analysis. Hum. Reprod. 27, 25–35 (2012).

    CAS  PubMed  Google Scholar 

  215. Tilley, A. E., Walters, M. S., Shaykhiev, R. & Crystal, R. G. Cilia dysfunction in lung disease. Annu. Rev. Physiol. 77, 379–406 (2015).

    CAS  PubMed  Google Scholar 

  216. Inaba, K. & Mizuno, K. Sperm dysfunction and ciliopathy. Reprod. Med. Biol. 15, 77–94 (2016).

    CAS  PubMed  Google Scholar 

  217. Serrano, C. J., Treviño, C. L., Felix, R. & Darszon, A. Voltage-dependent Ca(2+) channel subunit expression and immunolocalization in mouse spermatogenic cells and sperm. FEBS Lett. 462, 171–176 (1999).

    CAS  PubMed  Google Scholar 

  218. Santi, C. M., Darszon, A. & Hernandez-Cruz, A. A dihydropyridine-sensitive T-type Ca2+ current is the main Ca2+ current carrier in mouse primary spermatocytes. Am. J. Physiol. 271, C1583–C1593 (1996).

    CAS  PubMed  Google Scholar 

  219. Arnoult, C., Cardullo, R. A., Lemos, J. R. & Florman, H. M. Activation of mouse sperm T-type Ca2+ channels by adhesion to the egg zona pellucida. Proc. Natl Acad. Sci. USA 93, 13004–13009 (1996).

    CAS  PubMed  Google Scholar 

  220. Meizel, S. The sperm, a neuron with a tail: ‘neuronal’ receptors in mammalian sperm. Biol. Rev. Camb. Philos. Soc. 79, 713–732 (2004).

    PubMed  Google Scholar 

  221. Kurata, S., Hiradate, Y., Umezu, K., Hara, K. & Tanemura, K. Capacitation of mouse sperm is modulated by gamma-aminobutyric acid (GABA) concentration. J. Reprod. Dev. 65, 327–334 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Zeng, Y., Oberdorf, J. A. & Florman, H. M. pH regulation in mouse sperm: identification of Na(+)-, Cl(−)-, and HCO3(−)-dependent and arylaminobenzoate-dependent regulatory mechanisms and characterization of their roles in sperm capacitation. Dev. Biol. 173, 510–520 (1996).

    CAS  PubMed  Google Scholar 

  223. Singh, J. P., Babcock, D. F. & Lardy, H. A. Increased calcium-ion influx is a component of capacitation of spermatozoa. Biochem. J. 172, 549–556 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Ruknudin, A. & Silver, I. A. Ca2+ uptake during capacitation of mouse spermatozoa and the effect of an anion transport inhibitor on Ca2+ uptake. Mol. Reprod. Dev. 26, 63–68 (1990).

    CAS  PubMed  Google Scholar 

  225. Zhou, R., Shi, B., Chou, K. C., Oswalt, M. D. & Haug, A. Changes in intracellular calcium of porcine sperm during in vitro incubation with seminal plasma and a capacitating medium. Biochem. Biophys. Res. Commun. 172, 47–53 (1990).

    CAS  PubMed  Google Scholar 

  226. Baldi, E. et al. Intracellular calcium accumulation and responsiveness to progesterone in capacitating human spermatozoa. J. Androl. 12, 323–330 (1991).

    CAS  PubMed  Google Scholar 

  227. Zeng, Y., Clark, E. N. & Florman, H. M. Sperm membrane potential: hyperpolarization during capacitation regulates zona pellucida-dependent acrosomal secretion. Dev. Biol. 171, 554–563 (1995).

    CAS  PubMed  Google Scholar 

  228. Demarco, I. A. et al. Involvement of a Na+/HCO3− cotransporter in mouse sperm capacitation. J. Biol. Chem. 278, 7001–7009 (2003).

    CAS  PubMed  Google Scholar 

  229. Naz, R. K. & Rajesh, P. B. Role of tyrosine phosphorylation in sperm capacitation / acrosome reaction. Reprod. Biol. Endocrinol. 2, 75 (2004).

    PubMed  PubMed Central  Google Scholar 

  230. Neill, J. M. & Olds-Clarke, P. A computer-assisted assay for mouse sperm hyperactivation demonstrates that bicarbonate but not bovine serum albumin is required. Gamete Res. 18, 121–140 (1987).

    CAS  PubMed  Google Scholar 

  231. Cohen-Dayag, A., Tur-Kaspa, I., Dor, J., Mashiach, S. & Eisenbach, M. Sperm capacitation in humans is transient and correlates with chemotactic responsiveness to follicular factors. Proc. Natl Acad. Sci. USA 92, 11039–11043 (1995).

    CAS  PubMed  Google Scholar 

  232. Bleil, J. D. & Wassarman, P. M. Sperm-egg interactions in the mouse: sequence of events and induction of the acrosome reaction by a zona pellucida glycoprotein. Dev. Biol. 95, 317–324 (1983).

    CAS  PubMed  Google Scholar 

  233. Hino, T. et al. The behavior and acrosomal status of mouse spermatozoa in vitro, and within the oviduct during fertilization after natural mating. Biol. Reprod. 95, 50 (2016).

    PubMed  Google Scholar 

  234. La Spina, F. A. et al. Mouse sperm begin to undergo acrosomal exocytosis in the upper isthmus of the oviduct. Dev. Biol. 411, 172–182 (2016).

    PubMed  PubMed Central  Google Scholar 

  235. Jin, M. et al. Most fertilizing mouse spermatozoa begin their acrosome reaction before contact with the zona pellucida during in vitro fertilization. Proc. Natl Acad. Sci. USA 108, 4892–4896 (2011).

    CAS  PubMed  Google Scholar 

  236. Muro, Y. et al. Behavior of mouse spermatozoa in the female reproductive tract from soon after mating to the beginning of fertilization. Biol. Reprod. 94, 80 (2016).

    PubMed  Google Scholar 

  237. Sidhu, K. S. et al. A flow cytometric assay for global estimation of tyrosine phosphorylation associated with capacitation of spermatozoa from two marsupial species, the tammar wallaby (Macropus eugenii) and the brushtail possum (Trichosurus vulpecula). Reproduction 127, 95–103 (2004).

    CAS  PubMed  Google Scholar 

  238. Zoppino, F. C., Halón, N. D., Bustos, M. A., Pavarotti, M. A. & Mayorga, L. S. Recording and sorting live human sperm undergoing acrosome reaction. Fertil. Steril. 97, 1309–1315 (2012).

    PubMed  Google Scholar 

  239. Uhler, M. L., Leung, A., Chan, S. Y., Schmid, I. & Wang, C. Assessment of human sperm acrosome reaction by flow cytometry: validation and evaluation of the method by fluorescence-activated cell sorting. Fertil. Steril. 60, 1076–1081 (1993).

    CAS  PubMed  Google Scholar 

  240. Escoffier, J. et al. Flow cytometry analysis reveals that only a subpopulation of mouse sperm undergoes hyperpolarization during capacitation. Biol. Reprod. 92, 121 (2015).

    PubMed  PubMed Central  Google Scholar 

  241. Seifert, R. et al. The CatSper channel controls chemosensation in sea urchin sperm. EMBO J. 34, 379–392 (2015).

    CAS  PubMed  Google Scholar 

  242. Marquez, B. & Suarez, S. S. Bovine sperm hyperactivation is promoted by alkaline-stimulated Ca2+ influx. Biol. Reprod. 76, 660–665 (2007).

    CAS  PubMed  Google Scholar 

  243. Loux, S. C. et al. CatSper and the relationship of hyperactivated motility to intracellular calcium and pH kinetics in equine sperm. Biol. Reprod. 89, 123 (2013).

    PubMed  Google Scholar 

  244. Roldan, E. R. S. Assessments of sperm quality integrating morphology, swimming patterns, bioenergetics and cell signalling. Theriogenology 150, 388–395 (2020).

    CAS  PubMed  Google Scholar 

  245. Chang, H. & Suarez, S. S. Unexpected flagellar movement patterns and epithelial binding behavior of mouse sperm in the oviduct. Biol. Reprod. 86, 141–148 (2012).

    Google Scholar 

  246. Demott, R. P. & Suarez, S. S. Hyperactivated sperm progress in the mouse oviduct. Biol. Reprod. 46, 779–785 (1992).

    CAS  PubMed  Google Scholar 

  247. Suarez, S. S. Sperm transport and motility in the mouse oviduct: observations in situ. Biol. Reprod. 36, 203–210 (1987).

    CAS  PubMed  Google Scholar 

  248. Williams, M. et al. Sperm numbers and distribution within the human fallopian tube around ovulation. Hum. Reprod. 8, 2019–2026 (1993).

    CAS  PubMed  Google Scholar 

  249. Suarez, S. S. Interactions of spermatozoa with the female reproductive tract: inspiration for assisted reproduction. Reprod. Fertil. Dev. 19, 103–110 (2007).

    CAS  PubMed  Google Scholar 

  250. Ishikawa, Y., Usui, T., Yamashita, M., Kanemori, Y. & Baba, T. Surfing and swimming of ejaculated sperm in the mouse oviduct. Biol. Reprod. 94, 89 (2016).

    PubMed  Google Scholar 

  251. Xu, W. M. et al. Defective CFTR-dependent CREB activation results in impaired spermatogenesis and azoospermia. PLoS ONE 6, e19120 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Miyata, H. et al. Genome engineering uncovers 54 evolutionarily conserved and testis-enriched genes that are not required for male fertility in mice. Proc. Natl Acad. Sci. USA 113, 7704–7710 (2016).

    CAS  PubMed  Google Scholar 

  253. Suzuki, M., Mizuno, A., Kodaira, K. & Imai, M. Impaired pressure sensation in mice lacking TRPV4. J. Biol. Chem. 278, 22664–22668 (2003).

    CAS  PubMed  Google Scholar 

  254. Wedenoja, S. et al. A missense mutation in SLC26A3 is associated with human male subfertility and impaired activation of CFTR. Sci. Rep. 7, 14208 (2017).

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank Jae Yeon Hwang for valuable discussion and critical reading of the draft manuscript. This work was supported by start-up funds from Yale University School of Medicine, Grantham Foundation, and NIH (R01 HD 096745) to J.-J.C.

Author information

Authors and Affiliations

  1. Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA

    Huafeng Wang, Luke L. McGoldrick & Jean-Ju Chung

  2. Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA

    Jean-Ju Chung

Authors
  1. Huafeng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luke L. McGoldrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean-Ju Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched data for the article, made substantial contributions to discussion of content, and wrote, reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jean-Ju Chung.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Urology thanks P. Lishko, M. Yeste, Y. Okamura, P. Visconti and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

CatSper

Sperm-specific calcium channel.

NHEs

Sodium–hydrogen exchangers.

HV1

Proton channel.

KSper

Native sperm-specific potassium current/channel.

Na+/K+ ATPase

Sodium–potassium adenosine triphosphatase; also known as the sodium–potassium pump.

SLO3

The mediator of KSper, which is also used as the name of the protein or channel expressed heterologously.

Quadrilateral compartmentalization

The four linear Ca2+ signalling nanodomains.

DSper

Depolarizing channel of sperm.

TRPV4

Transient receptor potential cation channel subfamily V member 4.

P2X2

P2X purinoceptor 2.

Cav2.3

R type, voltage-dependent, calcium channel, α1E subunit.

PKD

Polycystin, transient receptor potential cation channel, autosomal dominant polycystic kidney disease protein.

PKDREJ

Polycystin family receptor for egg jelly.

CFTR

Cystic fibrosis transmembrane conductance regulator.

PMCA4

Plasma membrane calcium ATPase 4.

CNNM4

Cyclin and CBS domain divalent metal cation transport mediator 4.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, H., McGoldrick, L.L. & Chung, JJ. Sperm ion channels and transporters in male fertility and infertility. Nat Rev Urol 18, 46–66 (2021). https://doi.org/10.1038/s41585-020-00390-9

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-020-00390-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing