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Molecular Pharmacology

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Steroidal Antagonists of Progesterone- and PGE1-Induced Activation of the Cation Channel of Sperm (CatSper)

Erick J. Carlson, Gunda Ingrid Georg and Jon Eric Hawkinson
Molecular Pharmacology October 30, 2021, MOLPHARM-AR-2021-000349; DOI: https://doi.org/10.1124/molpharm.121.000349
Erick J. Carlson
1The Ohio State University, United States
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Gunda Ingrid Georg
2University of Minnesota, United States
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  • For correspondence: hawkinso@umn.edu
Jon Eric Hawkinson
3Medicinal Chemistry, University of Minnesota, United States
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  • For correspondence: hawkinso@umn.edu
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Abstract

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 E1 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 E1-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.

  • calcium channel blockers
  • Calcium channels
  • progesterone
  • prostaglandins
  • steroids
  • structure-activity relationships
  • © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
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Molecular Pharmacology: 101 (6)
Molecular Pharmacology
Vol. 101, Issue 6
1 Jun 2021
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Steroidal Antagonists of CatSper

Erick J. Carlson, Gunda Ingrid Georg and Jon Eric Hawkinson
Molecular Pharmacology October 30, 2021, MOLPHARM-AR-2021-000349; DOI: https://doi.org/10.1124/molpharm.121.000349

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Steroidal Antagonists of CatSper

Erick J. Carlson, Gunda Ingrid Georg and Jon Eric Hawkinson
Molecular Pharmacology October 30, 2021, MOLPHARM-AR-2021-000349; DOI: https://doi.org/10.1124/molpharm.121.000349
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