Structure of a mammalian sperm cation channel complex

Lin, Shuo; Ke, Meng; Zhang, Yuqi; Zhen, Yan; Wu, Jianping

doi:10.1038/s41586-021-03742-6

Cited by 52 publications

(74 citation statements)

References 55 publications

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“…Calcium entry drives hyperactivated motility (HAM) that is required for fertilization ( Quill et al, 2003 ; Qi et al, 2007 ). The recent cryo-electron microscopy structure of CatSper ( Lin et al, 2021 ) shows that the pore-forming subunits CatSper1–4 ( Ren et al, 2001 ; Quill et al, 2003 ; Qi et al, 2007 ) are stabilized by a pavilion-like structure consisting of the auxiliary subunits β ( Liu et al, 2007 ), γ ( Wang et al, 2009 ), δ ( Chung et al, 2011 ), and ε ( Chung et al, 2017 ) via their large extracellular domains. The ζ subunit ( Chung et al, 2017 ) and EF-Hand Calcium Binding Domain 9 ( Hwang et al, 2019 ) associate with the cytoplasmic face of the channel.…”

Section: Introductionmentioning

confidence: 99%

“…The ζ subunit ( Chung et al, 2017 ) and EF-Hand Calcium Binding Domain 9 ( Hwang et al, 2019 ) associate with the cytoplasmic face of the channel. Additional closely interacting transmembrane proteins are CatSper η , THEM249, and SLCO6C1 ( Lin et al, 2021 ). The expression and association of all CatSper subunits is required for channel function and fertilization.…”

Section: Introductionmentioning

confidence: 99%

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Steroidal Antagonists of Progesterone- and Prostaglandin E₁-Induced Activation of the Cation Channel of Sperm

2021

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The cation channel of sperm (CatSper) is the principal entry point for calcium in human spermatozoa and its proper function is essential for successful fertilization. As CatSper is potently activated by progesterone, we evaluated a range of steroids to define the structure-activity relationships for channel activation and found that CatSper is activated by a broad range of steroids with diverse structural modifications. By testing steroids that failed to elicit calcium influx as inhibitors of channel activation, we discovered that medroxyprogesterone acetate, levonorgestrel, and aldosterone inhibited calcium influx produced by progesterone, prostaglandin E 1 , and the fungal natural product l -sirenin, but these steroidal inhibitors failed to prevent calcium influx in response to elevated K + and pH. In contrast to these steroid antagonists, we demonstrated for the first time that the T-type calcium channel blocker ML218 acts similarly to mibefradil, blocking CatSper channels activated by both ligands and alkalinization/depolarization. These T-type calcium channel blockers produced an insurmountable blockade of CatSper, whereas the three steroids produced antagonism that was surmountable by increasing concentrations of each activator, indicating that the steroids selectively antagonize ligand-induced activation of CatSper rather than blocking channel function. Both the channel blockers and the steroid antagonists markedly reduced hyperactivated motility of human sperm assessed by computer-aided sperm analysis, consistent with inhibition of CatSper activation. Unlike the channel blockers mibefradil and ML218, which reduced total and progressive motility, medroxyprogesterone acetate, levonorgestrel, and aldosterone had little effect on these motility parameters, indicating that these steroids are selective inhibitors of hyperactivated sperm motility. SIGNIFICANCE STATEMENT The steroids medroxyprogesterone acetate, levonorgestrel, and aldosterone selectively antagonize progesterone- and prostaglandin E 1 -induced calcium influx through the CatSper cation channel in human sperm. In contrast to T-type calcium channel blockers that prevent all modes of CatSper activation, these steroid CatSper antagonists preferentially reduce hyperactivated sperm motility, which is required for fertilization. The discovery of competitive antagonists of ligand-induced CatSper activation provides starting points for future discovery of male contraceptive agents acting by this unique mechanism.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Steroidal Antagonists of Progesterone- and Prostaglandin E₁-Induced Activation of the Cation Channel of Sperm

2021

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“…It is composed of a hetero-tetrameric pore ( CATSPER1–4 ) associated with five auxiliary subunits (β, γ, δ, ε, ξ) that participate in stabilizing the complex, together with the pH-dependent Ca 2+ sensor EFCAB9 [ 50 , 51 ]. Additional components have been discovered over the last several years, among them, CATSPER η and the testis-specific organic anion transporter SLCO6C1, which led to the term “CatSpermasome” to name the channel-transporter super-complex that mediates Ca 2+ fluxes in sperm [ 52 ]. The CATSPER channel has been shown to mediate Ca 2+ during sperm motility and capacitation in a cAMP- and pH-dependent manner [ 53 ].…”

Section: Mutations In Ion Transporters and Channels That Results In H...mentioning

confidence: 99%

Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives

Cavarocchi

Whitfield

Saez

et al. 2022

IJMS

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In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle that provides the mechanical force for sperm propulsion and motility. Importantly several functional maturation events that occur during the journey of the sperm cells through the genital tracts are necessary for the activation of flagellar beating and the acquisition of fertilization potential. Ion transporters and channels located at the surface of the sperm cells have been demonstrated to be involved in these processes, in particular, through the activation of downstream signaling pathways and the promotion of novel biochemical and electrophysiological properties in the sperm cells. We performed a systematic literature review to describe the currently known genetic alterations in humans that affect sperm ion transporters and channels and result in asthenozoospermia, a pathophysiological condition defined by reduced or absent sperm motility and observed in nearly 80% of infertile men. We also present the physiological relevance and functional mechanisms of additional ion channels identified in the mouse. Finally, considering the state-of-the art, we discuss future perspectives in terms of therapeutics of asthenozoospermia and male contraception.

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“…The structure also opens a new doorway for male contraceptive design. We can now see the contours and folds of CatSper subunits, including those which are exposed to the external milieu at the mouse sperm surface (Lin et al, 2021). That latter group would likely be exploited as the druggable face of this target.…”

mentioning

confidence: 96%

“…Renewed hope for progress may emerge from a recent report by Shiyi Lin and coworkers in the July 29, 2021 issue of Nature (Lin et al, 2021). Mice were engineered in which one of the channel subunits, CatSper1, was tagged with both green fluorescent protein and with FLAG epitopes.…”

mentioning

confidence: 99%

Male contraception: Are we seeing the end of the beginning?

Florman

2021

Molecular Reproduction Devel

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Is there a graph more terrifying than that showing world population growth (Figure 1)? It now approaches 8,000 million (https://www. worldometers.info/world-population/) and although the growth rate may be slowing it has not yet plateaued. The United Nations estimates that it may level off at close to 11,000 million by 2100 (https://www.un.org/development/desa/en/news/population/ world-population-prospects-2017.html). In the wake of the increased population come elevated levels of poverty and food deprivation, environmental degradation, increased stresses on both population and individual health, and decreased biodiversity. There are pressing societal as well individual reasons to control human fertility. Female contraceptive pharmaceuticals, while imperfect, have been available in various forms for over half a century. Enovid, the first-generation combined oral contraceptive pill, was developed at the Worcester Foundation for Experimental Biology (now part of the University of Massachusetts Medical School), under the leadership of Gregory Pincus. It was first approved by the United States Food and Drug Administration for management of menstrual cycles in June 1957, and as a contraceptive in June 1960. Widespread availability in the United States only came in March 1972 after the US Supreme Court struck down a Massachusetts law that criminalized possession of contraceptives by unmarried people (Eisenstadt v. Baird, 405 U.S. 438; https://supreme.justia.com/cases/federal/us/405/438/).

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Structure of a mammalian sperm cation channel complex

Cited by 52 publications

References 55 publications

Steroidal Antagonists of Progesterone- and Prostaglandin E₁-Induced Activation of the Cation Channel of Sperm

Steroidal Antagonists of Progesterone- and Prostaglandin E₁-Induced Activation of the Cation Channel of Sperm

Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives

Male contraception: Are we seeing the end of the beginning?

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Structure of a mammalian sperm cation channel complex

Cited by 52 publications

References 55 publications

Steroidal Antagonists of Progesterone- and Prostaglandin E1-Induced Activation of the Cation Channel of Sperm

Steroidal Antagonists of Progesterone- and Prostaglandin E1-Induced Activation of the Cation Channel of Sperm

Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives

Male contraception: Are we seeing the end of the beginning?

Contact Info

Product

Resources

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Steroidal Antagonists of Progesterone- and Prostaglandin E₁-Induced Activation of the Cation Channel of Sperm

Steroidal Antagonists of Progesterone- and Prostaglandin E₁-Induced Activation of the Cation Channel of Sperm