Scientists have found a switch that triggers the ‘power kick’ sperms use to fertilise a human egg, uncovering a likely source of male infertility and a target for contraceptives that work in both men and women. The switch is a protein receptor that responds to the female sex hormone progesterone, which is released by the egg or oocyte, the ultimate goal towards which sperm swim.
Thousands of these receptors sit on the surface of a sperm’s tail and when the sperm gets close to the egg, the hormone activates the receptor and triggers a cascade of changes that make the tail snap like a whip, powering the sperm into and hopefully through the cells protecting the egg. “If the receptor protein doesn’t recognise progesterone, you would be infertile,” said Melissa Miller, a postdoctoral fellow at University of California, Berkeley. “This gives us an understanding of another pathway that is involved in human sperm activity,” Miller said.
A drug that inactivates this newly discovered receptor, however, might make a good “unisex” contraceptive - one that could be used by either sexual partner. Many tissues - the brain, the lungs, smooth muscle - contain related progesterone or steroid receptors that may work in a similar manner to trigger major changes in tissues, said Polina Lishko, assistant professor at UC Berkeley.
“Now that we know the players, the next step is to look in other tissues that express these proteins to see whether progesterone acts on them in a similar manner to affect pain threshold adjustment in pain sensing neurons, surfactant production in the lungs or the excessive smooth muscle contractions found in asthma,” Lishko said.
Today, doctors are unable to determine the cause of nearly 80% of all cases of male infertility, in part because little is known about the many molecular steps involved in the production of sperm and its interactions with the egg.
Researchers used a new technique that allows them to stick electrodes on a sperm’s tail and record its reactions to hormones, key to probing the molecular cascades that govern sperm behaviour. This led to the discovery that a large receptor on sperm tails - a calcium channel dubbed CatSper - is activated by progesterone from the egg.
Progesterone unlocks the channel gate, letting electrically charged calcium atoms flood into the cell. This leads to a biochemical cascade that readies the sperm cell for its last-ditch effort to fertilise the oocyte. Researchers showed that progesterone actually binds to a previously mysterious enzyme called ABHD2, which is found at high levels in sperm.
Once progesterone binds to the enzyme, which sits on the surface of the sperm, it removes a lipid (2AG) that has been inhibiting the calcium channel. Released of inhibition, CatSper opens the gate to calcium ions and eventual sperm activation. The research was published in the journal Science.