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

The sperm-specific Ca(2+) channel CatSper registers chemical cues that assist human sperm to fertilize the egg. Prime examples are progesterone and prostaglandin E(1) 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 Ca(2+) 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 Ca(2+) increase that invariably rests on Ca(2+) 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 Zn(2+) 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.