The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn2+ on CatSper Ca2+ Channels in Human Sperm

Abstract

The sperm-specific Ca2+ channel CatSper registers chemical cues that assist human sperm to fertilize the egg. Prime examples are progesterone and prostaglandin E1 that activate CatSper without involving classical nuclear and G protein-coupled receptors, respectively. Here, we study the action of seminal and follicular fluid as well of the contained individual prostaglandins and steroids on the intracellular Ca2+ concentration of sperm from donors and CATSPER2-deficient patients that lack functional CatSper channels. We show that any of the reproductive steroids and prostaglandins evokes a rapid Ca2+ increase that invariably rests on Ca2+ influx via CatSper. The hormones compete for the same steroid- and prostaglandin-binding site to activate the channel, respectively. Analysis of the hormones’ structure–activity relationship highlights their unique pharmacology in sperm and the chemical features determining their effective properties. Finally, we show that Zn2+ suppresses the action of steroids and prostaglandins on CatSper, which might prevent premature prostaglandin activation of CatSper in the ejaculate, aiding sperm to escape from the ejaculate into the female genital tract. Altogether, our findings reinforce that human CatSper serves as a promiscuous chemosensor that enables sperm to probe the varying hormonal microenvironment prevailing at different stages during their journey across the female genital tract.

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

“…The endogenous steroid hormones testosterone and 17 β -estradiol ( 36 and 37 ) had moderate potency for eliciting sperm calcium uptake, consistent with previous reports ( Blackmore et al, 1990 ; Brenker et al, 2018b ; Rehfeld et al, 2020 ; Jeschke et al, 2021 ), but contrasting with another study that found no CatSper activation by these steroids ( Mannowetz et al, 2017 ). Given the activity of testosterone, 11 β -methyl-19-nortestosterone (11 β -MNT, 38 ) and 7 α -methyl-19-nortestosterone (7 α -MNT, 39 ) were tested.…”

“…The observed steroid SAR, including the low activity of steroids with modified D rings, is consistent with previous studies of steroid-induced calcium influx ( Blackmore et al, 1990 ; Jeschke et al, 2021 ). Interestingly, several steroid activators were shown to activate CatSper by binding to the same site ( Jeschke et al, 2021 ).…”

“…Bulky modifications of the D-ring of the scaffold produce a much greater diminution of activity, suggesting that this portion of the steroid plays an important role in CatSper activation. Whereas 17 α -hydroxylation ( 25 ) reduced activity slightly consistent with previous reports ( Blackmore et al, 1990 ; Jeschke et al, 2021 ), calcium influx is largely or completely ablated for compounds with other modifications at the C17 position ( 4 , 29 , 34, 35 ), particularly when combined with changes at the C18 position ( 5, 6 ), and for the C20 ketalized steroids. The observed steroid SAR, including the low activity of steroids with modified D rings, is consistent with previous studies of steroid-induced calcium influx ( Blackmore et al, 1990 ; Jeschke et al, 2021 ).…”

“…Whereas 17 α -hydroxylation ( 25 ) reduced activity slightly consistent with previous reports ( Blackmore et al, 1990 ; Jeschke et al, 2021 ), calcium influx is largely or completely ablated for compounds with other modifications at the C17 position ( 4 , 29 , 34, 35 ), particularly when combined with changes at the C18 position ( 5, 6 ), and for the C20 ketalized steroids. The observed steroid SAR, including the low activity of steroids with modified D rings, is consistent with previous studies of steroid-induced calcium influx ( Blackmore et al, 1990 ; Jeschke et al, 2021 ). Interestingly, several steroid activators were shown to activate CatSper by binding to the same site ( Jeschke et al, 2021 ).…”

Sperm-Guiding Unconventional Prostaglandins in C. elegans: Synthesis and Signaling

“…PGs such as PGE1 potentiates CatSper at the low concentrations through binding sites other than that of progesterone and how the combined action of progesterone and PGs influences sperm function remains to be established [47,94,95]. In mammalian system, PGE2-EP2 signaling activates chemokines CCL-7 signaling which facilitates sperm migration to the cumulus egg complex and integrin-mediated cumulus extracellular matrix (ECM) assembly helps sperm to penetrate the oocyte [85].…”