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Sperm ion channels and transporters in male fertility and infertility

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.

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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.

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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.

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

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Correspondence to Jean-Ju Chung.

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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.

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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

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