Researchers funded by the National Institutes of
Health have discovered the cellular switch that
boosts the activity of sperm cells so that they can
travel to the egg. The finding may lead to new
options for male contraception as well as treatments
for infertility resulting from problems with sperm
mobility.
Inside the male reproductive tract, mature sperm are
capable of limited movement. This limited movement,
however, is not enough to propel them toward the egg
when they enter the female reproductive tract. To
begin their journey, they must first be activated by
the hormone progesterone, which is released by the
egg.
Publishing online in Science, the researchers report
that the molecule to which progesterone must bind is
the enzyme alpha/beta hydrolase domain containing
protein 2 (ABHD2), found in the sperm cell’s outer
membrane. The study was conducted by Melissa R.
Miller and colleagues at the University of
California, Berkley, the University of California,
San Francisco, and Yale University School of
Medicine in New Haven, Connecticut.
“This is an important advance in explaining how
sperm become 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.”
Similarly, strategies to bypass or enhance the
enzyme might provide therapies for treating
infertility resulting from sperm that lack movement
capability.
Before a sperm can transition to the hyper-active
phase, calcium must pass through the cell’s outer
membrane and enter the flagella, the tail-like
appendage the cell uses to propel itself. The sperm
protein known as CatSper joins with similar proteins
in the flagella to allow the entry of calcium.
Researchers show that ABHD2 is highly expressed in
spermatozoa, binds progesterone, and acts as
progesterone-dependent lipid hydrolase by depleting
endocannabinoid 2-arachidonoylglycerol (2AG) from
plasma membrane. 2AG inhibits sperm calcium channel
CatSper, and 2AG removal leads to calcium influx via
CatSper and ensures sperm activation.
When the researchers undertook the current study, it
was not known whether progesterone interacted
directly with CatSper to trigger the calcium influx,
or acted on some other molecule (which, in turn,
acted on CatSper). Before treating sperm with
progesterone, the researchers exposed them to a
chemical that inhibits a particular class of enzymes
that they believed could include the candidate
molecule that acted on CatSper. The hunch proved
correct: the treated cells remained inactive after
progesterone exposure, indicating that CatSper was
not directly involved.
Working with modified progesterone, the researchers
eventually isolated ABHD2 from the sperm tails. When
the researchers inactivated ABHD2, exposure to
progesterone failed to activate the sperm cells,
confirming that ABHD2 is the molecular target for
progesterone.
For more information
Science
Unconventional endocannabinoid signaling governs
sperm activation via sex hormone progesterone
Melissa R. Miller, Nadja Mannowetz, Anthony T.
Iavarone, Rojin Safavi, Elena O. Gracheva, James F.
Smith, Rose Z. Hill, Diana M. Bautista, Yuriy
Kirichok, Polina V. Lishko
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Yale School of Medicine
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University of California
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Eunice Kennedy Shriver National Institute of Child
Health and Human Development (NICHD)
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National Institutes of Health (NIH)
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