March 29, 2016

How sperm are activated

At a Glance

  • Researchers identified a molecular pathway that primes sperm to fertilize an egg.
  • The findings could inform development of male contraceptives and infertility treatments.
Sperm approaching an egg. Sperm need a surge in activity to penetrate the tough outer layer of an egg. Eraxion/iStock/Thinkstock

Many different factors can affect a couple’s ability to conceive. Fertility issues can arise for men if there are problems with the number, shape, or movement of sperm. These glitches can make it hard for the sperm to fertilize an egg.

Once inside the female reproductive tract, sperm use their tail-like appendages to swim for the egg. A chemical signal around the egg called progesterone boosts the sperm’s movements into a “hypermotile” state. Tail movements become stronger and able to generate more swimming force. Sperm need this surge in activity to penetrate the tough outer layer of an egg.

To understand how this heightened activity is turned on, a team led by Dr. Polina V. Lishko at the University of California, Berkley, searched for the sperm molecule that detects the egg’s chemical signal. The study was funded in part by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). Results were published online on March 17, 2016, in Science.

After the sperm detects progesterone, calcium rushes in through the tail’s outer membrane. A protein called CatSper sits in the membrane and acts as a gateway for calcium. The scientists investigated whether progesterone works directly through CatSper or if it opens the channel by working through another molecule. They measured CatSper activity in sperm cells treated with a drug that shuts down a class of enzymes they believed might be responsible for progesterone effects: metabolic serine hydrolases (mSH), which play a role in signaling pathways within lipid membranes.

Their hunch proved correct: the treated cells didn’t show progesterone-induced CatSper activity or change sperm motility. But the treatment didn’t affect baseline CatSper activity. The results suggested that progesterone works with a partner to open the way for calcium.

The group then searched for candidate partner proteins. They zeroed in on alpha/beta hydrolase domain-containing protein 2 (ABHD2). When the researchers blocked ABHD2 activity using specific antibodies, progesterone-induced CatSper activity and calcium entry decreased. The result confirmed that ABHD2 is the molecular target for progesterone.

The group showed that when progesterone is present, ABHD2 degrades endocannabinoid molecules in the plasma membrane. These keep CatSper closed, so their removal causes calcium to rush in and activate sperm.

“This is an important advance in explaining how sperm become hypermotile in the female reproductive tract,” explains Dr. Stuart Moss, director of the male reproductive health program at NICHD.

These findings may lead to new approaches for male contraception and treatments for infertility that result from problems with sperm mobility.

Related Links

Reference: Unconventional endocannabinoid signaling governs sperm activation via sex hormone progesterone. Miller MR, Mannowetz N, Iavarone AT, Safavi R, Gracheva EO, Smith JF, Hill RZ, Bautista DM, Kirichok Y, Lishko PV. Science. 2016 Mar 17; Epub ahead of print. doi: 10.1126/science.aad6887. PMID: 26989199.

Funding: NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of General Medical Sciences (NIGMS), and National Center for Research Resources (NCRR).