Researchers from the University of California, Berkeley have recently published data that could contribute significantly to the development of a unisex contraceptive. The investigators found the switch that triggers the power kick sperm use to penetrate and fertilize a human egg—which may also be an important source of male infertility.
The molecular switch that the UC Berkeley scientists discovered is a protein receptor that responds to the female sex hormone progesterone, which is released by the egg or oocyte with the ultimate goal of attracting sperm to swim toward the cell. The researchers knew that thousands of these receptors sit on the surface of a sperm's tail, but they discovered that when the sperm gets close to the egg, the hormone activates the receptor and triggers a cascade of changes, making the tail snap like a whip, powering the sperm into and hopefully through the egg's surface.
“If the receptor protein doesn't recognize progesterone, you would be infertile,” explained lead study author Melissa Miller, Ph.D., postdoctoral fellow at both UC Berkeley and UC San Francisco. “This gives us an understanding of another pathway that is involved in human sperm activity.”
The findings from this study were published recently in Science in an article entitled “Unconventional Endocannabinoid Signaling Governs Sperm Activation via Sex Hormone Progesterone.”
“What's really cool is that we have an actual target for unisex contraceptive development,” Dr. Miller remarked. “If you can stop progesterone from inducing a power stroke, sperm are not going to be able to reach or penetrate the oocyte.”
Although there are other possible targets for a contraceptive that would prevent the initiation of the power stroke, called hyperactivation, or the simultaneous release of enzymes that cut through the protective layer around the egg, “this is one of the better options we have for a unisex contraceptive,” Dr. Miller added.
Interestingly, many tissues within the human body contain related progesterone or steroid receptors and could work in a similar manner to trigger significant changes within these tissues.
“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,” said senior study author Polina Lishko, Ph.D., assistant professor of molecular and cell biology at UC Berkeley. “This may be a universal pathway in all cells.”
The UC Berkeley team was very interested in drilling down the precise molecular mechanisms that cause the hyperactivation of the sperm cells because it also has significant implications for male infertility. This led the investigators to discover that the progesterone-activated receptor on the sperm's tail was a calcium ion channel called CatSper. The flood of calcium ions into the sperm cell activates a biochemical cascade that readies the sperm cell for its last-ditch effort to fertilize the oocyte.
However, the researchers suspected that that progesterone was not acting directly on the calcium channel, but on some other receptor that, in turn, activated the calcium channel. They proved this hypothesis by showing that progesterone actually binds to an enzyme called ABHD2, found at high levels in sperm. Once progesterone binds to the enzyme, which sits on the surface of the sperm, it removes a lipid—2-arachidonoylglycerol (2AG)—that has been inhibiting the calcium channel, ultimately leading to sperm activation. The inhibitor of the calcium channel CatSper is probably there for good reason—to prevent sperm from prematurely sprinting toward the egg and using up their limited supply of energy.
“People tend to think of fertilization as like a marathon, where the fastest, most powerful sperm is going to win,” Dr. Miller noted. “We think of it like the Tour de France, where the riders in front are blocking the wind for the actual winner. Fertilization is a team sport, where the first sperm clears the way, expending their energy to break through the barrier cells so that the slow and steady guy can get into the oocyte.”
The study also sheds light on a long-standing mystery about steroids like progesterone: Why they appear to act in two distinctly different ways.
“This is an important advance in explaining how sperm becomes hypermotile in the female reproductive tract,” said Stuart Moss, Ph.D., director of the male reproductive health program at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development, which funded the study. “Developing new compounds that block ABHD2 ultimately may yield new contraceptive methods to prevent sperm from reaching the egg.”