CatSper solves mystery of progesterone action on sperm

Groundbreaking research has provided the answer to a long-standing conundrum of reproductive biology: how does progesterone exert its rapid effects on human sperm during fertilization? The missing link turns out to be the cation channel of sperm (better known as 'CatSper'). This basic science discovery could translate into real clinical advances for human fertility research.

In somatic cells, progesterone crosses the plasma membrane, binds to its nuclear receptor and regulates gene expression—a process that can take several hours. By contrast, exposure to progesterone causes instantaneous influx of Ca²⁺ into sperm cells, which are transcriptionally and translationally silent. This rapid response suggests the presence of an alternative signaling pathway in sperm that does not involve the classic progesterone receptor. However, the identity of the molecules involved remained a mystery.

Two research groups—one in Bonn and the other in San Francisco—had been working independently on this issue for some years. After a chance encounter at a scientific conference, the two groups agreed to share information and publish their findings back-to-back. A key component of the investigation was the availability of state-of-the art optical and electrophysiological techniques. Timo Strünker and colleagues in Bonn employed kinetic fluorimetric approaches to study progesterone-evoked Ca²⁺ signals on the millisecond timescale after rapid mixing of sperm with progesterone. In addition, the patch–clamp technique was used by both teams and allowed direct recording of ionic currents flowing across human sperm cells.

“The patch–clamp technique was essential for identification of CatSper as the Ca²⁺ channel activated by progesterone,” explains Yuriy Kirichok of the University of California, San Francisco, who was the first to apply this technique to sperm. “It allowed detailed comparison of the electrophysiological fingerprint of the progesterone-activated current with that of CatSper. Everything, including ion selectivity, activation by intracellular alkalinization, voltage-dependence, pharmacology and subcellular localization (flagellum), coincided.”

The researchers found that human CatSper is strongly activated by progesterone, as well as by alkaline pH and certain prostaglandins. These effects occurred in the absence of intracellular Ca²⁺, ATP or GTP, a surprising finding that excluded the involvement of second messengers or activation of metabotropic receptors in the signaling pathway. In addition, the use of a potent antagonist of the classic progesterone receptor did not affect progesterone-mediated activation of CatSper, indicating that the progesterone-binding site associated with CatSper is pharmacologically different from that of the nuclear receptor. Moreover, the two groups discovered novel CatSper channel blockers, which inhibited the effects of progesterone on CatSper.

The next step for Strünker's team is to exploit the chemical inhibitors of CatSper. “These inhibitors will allow us to study the role of progesterone and CatSper in fertilization in detail. In addition, our work suggests that CatSper channels control chemotaxis in human sperm. So far, CatSper has only been implicated in sperm hyperactivation,” he explains. Kirichok plans to focus on elucidating the progesterone-binding domain associated with CatSper. “Once we identify this domain, it will facilitate discovery of selective antagonists that can be potentially used as nonhormonal contraceptives.”