Sperm protein may lead to male pill.

Faced with countless competitors, a human sperm must be a world-class swimmer to win the race to an egg and fertilize it first. Scientists have now found a protein that helps a mammalian sperm wiggle its long tail to speed along.

Mutations in the gene for this protein, which appears to permit calcium ions to enter the sperm's tail, may account for some cases of male infertility. By rendering sperm immobile, a drug that inhibits the protein could serve as a male version of the birth control pill.

"Theoretically, [the protein] would be an ideal target for a male contraceptive," says David E. Clapham of the Howard Hughes Medical Institute at Children's Hospital in Boston.

Clapham and his colleagues came upon this reproductive protein during their search for new channels that govern the flow of calcium, sodium, and other ions in and out of cells. Such channels are present in every cell in the body and are vital to each cell's function.

While searching through a database of unidentified DNA sequences, the researchers found one that appeared to encode a new calcium channel. As an initial step to studying the role of the protein, they made antibodies to detect it in Samples of dozens of mouse and human tissues.

"It turned out to be the most highly localized protein I've ever seen," says Clapham. "It's only present in sperm, as far as we can tell."

The investigators next created mice with inactive copies of the gene for the putative ion channel. While the mice were otherwise healthy and the females were fertile, the male mice turned out to be 100 percent infertile, Clapham's team reports in the Oct. 11 NATURE.

Further investigation revealed that sperm from the mutant mice were poor swimmers compared with normal sperm and couldn't fertilize normal mouse eggs. "The sperm could not penetrate the layer around an egg, the zona pellucida," says Clapham.

Finally, the scientists used calcium-sensitive dyes to investigate whether the ion channel is defective in the mutant mice. When they stimulated sperm tails in a way that normally causes an influx of calcium, "there was no rise in calcium in the mutant mice's sperm," notes Clapham.

Infertile men who have immotile sperm may have mutations in the gene for this ion channel. "If you can show me that this really causes infertility in humans, then I would view it as a more promising target [for a male contraceptive] than the other channels we've seen," says Susan Benoff of North Shore University Hospital in Manhasset, N.Y.

Benoff has for many years investigated whether calcium channel blockers commonly prescribed for high blood pressure and heart disease can serve as male contraceptives. The drugs can render men infertile, she has found.

The prescribed blockers alter cholesterol synthesis in sperm, preventing them from penetrating the zona pellucida, Benoff contends. She doesn't think that the drugs act upon the newly discovered ion channel because men taking the drugs have sperm with normal motility.

The absence of the protein in normal tissues other than sperm suggests that drugs that inhibit the channel wouldn't produce side effects in men. Women could take such a blocker to inactivate a partner's sperm, Clapham speculates.

Still, scientists caution that crafting a safe contraceptive will be an arduous process. "It's very hard to design a calcium channel blocker that is going to work for just one channel," notes Benoff.

Nevertheless, the idea of a reversible, nonhormonal method of shutting down male fertility is "very appealing," says Tracy Rankin of the National Institute for Child Health and Development in Bethesda, Md., which funds research into male contraception (SN: 9/30/00, p. 222).

"There's a lot of work to be done, but this is an exciting first step," she says.