Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids
Edited by David E. Clapham, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, and approved April 20, 2017 (received for review January 10, 2017)
Letter
January 5, 2018
Science Sessions podcast
June 11, 2019
Significance
The calcium channel of sperm—CatSper—is vital for male fertility. CatSper is activated by the hormone progesterone, but its pharmacological profile is not well studied. By exploring steroid selectivity of CatSper activation, we found one additional agonist—pregnenolone sulfate—and the two plant-derived inhibitors pristimerin and lupeol. By averting sperm hyperactivation, both inhibitors can prevent fertilization, thus acting as contraceptive agents. Additionally, by exploring CatSper regulation by endogenous steroids, we explain why CatSper is silent within the male reproductive tract and is only activated in close proximity to the egg. Interestingly, both testosterone and hydrocortisone antagonize the action of progesterone at physiological concentrations, which may explain why elevated levels of these steroids in the female organism affect fertility.
Abstract
The calcium channel of sperm (CatSper) is essential for sperm hyperactivated motility and fertility. The steroid hormone progesterone activates CatSper of human sperm via binding to the serine hydrolase ABHD2. However, steroid specificity of ABHD2 has not been evaluated. Here, we explored whether steroid hormones to which human spermatozoa are exposed in the male and female genital tract influence CatSper activation via modulation of ABHD2. The results show that testosterone, estrogen, and hydrocortisone did not alter basal CatSper currents, whereas the neurosteroid pregnenolone sulfate exerted similar effects as progesterone, likely binding to the same site. However, physiological concentrations of testosterone and hydrocortisone inhibited CatSper activation by progesterone. Additionally, testosterone antagonized the effect of pregnenolone sulfate. We have also explored whether steroid-like molecules, such as the plant triterpenoids pristimerin and lupeol, affect sperm fertility. Interestingly, both compounds competed with progesterone and pregnenolone sulfate and significantly reduced CatSper activation by either steroid. Furthermore, pristimerin and lupeol considerably diminished hyperactivation of capacitated spermatozoa. These results indicate that (i) pregnenolone sulfate together with progesterone are the main steroids that activate CatSper and (ii) pristimerin and lupeol can act as contraceptive compounds by averting sperm hyperactivation, thus preventing fertilization.
Acknowledgments
We thank Dr. Yuriy Kirichok for help with the testosterone measurements (Protocol CS084484); Dr. James F. Smith and Liza Jalalian of the Center for Reproductive Health (Urology Department, University of California, San Francisco) for their support with the CASA measurements; and Ida Bjoerkgren for her help with pilot experiments. This work was supported by NIH Grants R01GM111802 and R21HD081403, Pew Biomedical Scholars Award 00028642, Alfred P. Sloan Award FR‐2015‐65398, and Packer Wentz Endowment Will (to P.V.L.).
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Information & Authors
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Cover image: Pictured is a folded hindwing in a ladybird beetle [Coccinella septempunctata (L.)]. Kazuya Saito et al. studied the process of hindwing folding in ladybird beetles and determined that the wing cases and supporting veins in folding play important roles in the process. In particular, the veins function like tape springs that allow the wings to be foldable, yet stiff when unfolded. The findings could inform the design of stable, deployable structures. See the article by Saito et al. on pages 5624–5628. Image courtesy of Kazuya Saito.
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Freely available online through the PNAS open access option.
Submission history
Published online: May 15, 2017
Published in issue: May 30, 2017
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Acknowledgments
We thank Dr. Yuriy Kirichok for help with the testosterone measurements (Protocol CS084484); Dr. James F. Smith and Liza Jalalian of the Center for Reproductive Health (Urology Department, University of California, San Francisco) for their support with the CASA measurements; and Ida Bjoerkgren for her help with pilot experiments. This work was supported by NIH Grants R01GM111802 and R21HD081403, Pew Biomedical Scholars Award 00028642, Alfred P. Sloan Award FR‐2015‐65398, and Packer Wentz Endowment Will (to P.V.L.).
Notes
This article is a PNAS Direct Submission.
Authors
Competing Interests
Conflict of interest statement: P.V.L. and N.M. are inventors on a patent application filed by University of California, Berkeley related to the work presented in this paper.
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