The Action of Reproductive Fluids and Contained Steroids, Prostaglandins, and Zn(2+) on CatSper Ca(2+) Channels in Human Sperm.

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.

Jeschke JK ，Biagioni C ，Schierling T ，Wagner IV ，Börgel F ，Schepmann D ，Schüring A ，Kulle AE ，Holterhus PM ，von Wolff M ，Wünsch B ，Nordhoff V ，Strünker T ，Brenker C ... -  《Frontiers in Cell and Developmental Biology》

The sperm-specific K(+) channel Slo3 is inhibited by albumin and steroids contained in reproductive fluids.

Lorenz J ，Eisenhardt C ，Mittermair T ，Kulle AE ，Holterhus PM ，Fobker M ，Boenigk W ，Nordhoff V ，Behre HM ，Strünker T ，Brenker C ... -  《Frontiers in Cell and Developmental Biology》

The action of physiological and synthetic steroids on the calcium channel CatSper in human sperm.

Wehrli L ，Galdadas I ，Voirol L ，Smieško M ，Cambet Y ，Jaquet V ，Guerrier S ，Gervasio FL ，Nef S ，Rahban R ... -  《Frontiers in Cell and Developmental Biology》

The CatSper channel: a polymodal chemosensor in human sperm.

Brenker C ，Goodwin N ，Weyand I ，Kashikar ND ，Naruse M ，Krähling M ，Müller A ，Kaupp UB ，Strünker T ... -  《-》

Steroidal Antagonists of Progesterone- and Prostaglandin E(1)-Induced Activation of the Cation Channel of Sperm.

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.

Carlson EJ ，Georg GI ，Hawkinson JE 《-》