The potential for the development of a contraceptive that works in both men and women is on the horizon as biologists at the University of California, Berkeley have discovered the mechanism used by sperm cells to penetrate and fertilize a human oocyte.
As the sperm cell swims towards the egg cell, a “power kick” is triggered upon detection of the female sex hormone progesterone which is secreted by the egg cell. The switch that then activates this response is a protein receptor that reacts to the presence of progesterone; thousands of receptors are located on the surface of the sperm’s tail. As the sperm cell approaches the egg cell, these receptors activate in response to the female sex hormone and cause the flagella to snap swiftly like a whip as opposed to moving in its normal sinusoidal motion, propelling the sperm forward through the egg’s outer layer of protective cells.
“What’s really cool is that we have an actual target for unisex contraceptive development”, said Melissa Miller, a postdoctoral fellow at both UC Berkeley and UC San Francisco and the first author of a paper reporting the discovery, “This gives us an understanding of another pathway that is involved in human sperm activity.”
Finding a drug that is able to inactivate this receptor would cause sperm cells to lose their ability to penetrate or get close enough to penetrate the oocyte, resulting in an effective contraceptive that can be used by either partner regardless of sex. Hyperactivation is the term used to describe the initiation of the power stroke which is the simultaneous release of enzymes that pierce through the protective layer of cells around the oocyte.
Many tissues such as the brain, the lungs, and smooth muscle have progesterone or steroid receptors that might function in a similar manner as the receptors in sperms cells that cause major changes in 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 UC Berkeley assistant professor of molecular and cell biology Polina Lishko. “This may be a universal pathway in all cells.”
The inability of the receptor protein to recognize progesterone could be a cause of infertility in males. Almost 80 percent of all cases of male infertility are unknown because we have little knowledge of egg-sperm interactions and the molecular steps involved in sperm production (Sanders, 2016). The use of federal funds for research that involves putting eggs and sperm together in the same dish is not allowed by the United States government, so much is unknown about how their interactions cause infertility. It is suspected that half of all cases of infertility may be due to defects in sperm cells.
Using only traditional lab techniques made the study of sperm very difficult for researchers; however, the techniques that were engineered at USCF and UC Berkeley by Polina Lishko and her colleague Yuriy Kirichok allowed them to discover the sperm’s power kick switch. These techniques made it possible for them to attach electrodes on a sperm cell’s flagella and monitor its reactions to hormones, which was essential for analyzing the “molecular cascades that govern sperm behavior” (Sanders, 2016). Using this technique, they discovered that a calcium channel named CatSper found on sperm tails responds to progesterone secreted from the egg. Electrically charged calcium atoms are released into the cell once the channel gates are opened by the progesterone, resulting in a biochemical cascade that prepares the sperm cell for the final kick to fertilize the egg cell.
However, it turns out that the calcium channel was not activated by progesterone directly but by another receptor which in turn activated CatSper; Miller and Lishko demonstrated that progesterone actually binds to the enzyme ABHD2, which is found in high concentrations on the surface of the sperm cell. Upon binding to ABHD2, the female sex hormone removes a lipid, 2AG, which acts as an inhibitor to the calcium channel. According to Miller, the lipid inhibitor most likely prevents the sperm from rushing towards the egg prematurely and wasting its limited supply of energy. Once uninhibited, CatSper freely opens the calcium ion gate leading to the activation of the power stroke.
The findings of this study also reveal more about steroids like progesterone and offer deeper insight as to why they seem to act in two completely different ways. Progesterone is usually the catalyst of a cascade of processes in the cell that modify gene expression in the nucleus in a process, which can take days to complete. However, the female sex hormone sometimes generates rapid changes in the cell, called non-genomic steroid signaling, using a different process that is much faster than gene expression.
Lishko studies the sperm of many mammals such as rats, mice, bulls, and boars in addition to humans in order to gain a better understanding of the fertilization process across various species, and she says that sperm are perfect for analyzing non-genomic steroid signaling because “the genes in sperm are silenced and the normal type of steroid signaling is not present” (Sanders, 2016). Once the basics of steroid signaling are discovered in sperm, other types of cells may be studied using the same process.
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Editor: Shreya Singireddy