Regulation of the sperm calcium channel CatSper by endogenous steroids and plant triterpenoids
Nadja Mannowetz a, Melissa R. Miller a, and Polina V. Lishko a,1
aDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720
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)
Source/Fonte: WebMD
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.
CatSper steroids lupeol triterpenoids pristimerin
Footnotes
1To whom correspondence should be addressed. Email: lishko{at}berkeley.edu.
Author contributions: N.M. and P.V.L. designed research; N.M., M.R.M., and P.V.L. performed research; N.M. contributed new reagents/analytic tools; M.R.M. helped with pilot experiments; P.V.L. led the research study; N.M. and P.V.L. analyzed data; and N.M. and P.V.L. wrote the paper.
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.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1700367114/-/DCSupplemental.
Freely available online through the PNAS open access option.
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