Male Fertility
Researchers at Children's Hospital Boston and the Howard Hughes Medical Institute have, for the first time, captured the electrical activity of a single sperm cell. The technically difficult maneuver, reported in the February 9 Nature, allows the first measurement of the currents that flow across the sperm's outer membrane.
The ability to measure sperm currents has also enabled the researchers to pin down the role of a protein called CatSper that is vital for male fertility: establishing CatSper as a target for developing a male contraceptive.
CatSper, discovered in 2001 in the Children's Hospital Boston lab of David Clapham, MD, PhD, is found only in the tails of mature sperm. Mice that lacked CatSper were completely infertile: their sperm were poor swimmers and couldn't penetrate the protective barriers around the egg. But no one was sure what role CatSper played or how it worked.
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By directly measuring electrical activity, the new experiments, conducted by Yuriy Kirichok, PhD and Betsy Navarro, PhD, were able to show that CatSper is a key channel by which calcium ions enter the sperm's tail. The calcium influx, measurable as an electrical current, "hyperactivates" the tail's motor proteins, giving the sperm the burst of swimming power needed to reach the egg. The current was detectable in sperm from normal mice, but not in sperm from mice that lacked CatSper.
"Now, people can directly test modulators of CatSper," Navarro says. "If they find something that blocks the current, it could be used as a male contraceptive. Before, people didn't know what the exact target was, and didn't have a system to test drugs."
Hydra Biosciences (Cambridge, Mass.), a biotech company co-founded by Clapham, is pursuing a drug that would block CatSper. The challenge will be to develop a drug that blocks only CatSper and not other calcium channels, which occur throughout the body.
Electrical activity has long been known to be important in sperm cells, and scientists had tried unsuccessfully to measure electrical currents in sperm since 1985, says Kirichok. Because the sperm's outer membrane is tightly linked to rigid structures inside the cell, researchers - including Kirichok and Navarro - couldn't get a tight seal between the membrane and the pipette used to measure the currents.
But then, studying electron microscopy images of sperm, Kirichok noticed a tiny bubble on the sperm's tail, not far from the head. Its function is unknown, but it's believed to be shed when a sperm is ejaculated. Kirichok found that the bubble had enough "give" in it to form a tight contact with the pipette so he could measure electrical currents, a technique known as patch-clamping.
Further testing indicated that CatSper is triggered by alkaline conditions inside the sperm cell to open its "gates" to calcium. The next step is to find out what causes these alkaline conditions. "Quite possibly the sperm senses something released by the egg," Kirichok says.
The ability to patch-clamp sperm and measure its electrical activity will also allow the researchers to study other channels that regulate sperm behavior. For example, the sperm head also contains calcium channels whose identity and functions are unknown. The channels may help the sperm release enzymes that dissolve the barrier around the egg, Kirichok says.
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