Protein Link Between Brain/Heart Function and Fertility

Carmen J. Williams, M.D., Ph.D. Principal Investigator National Institute of Environmental Interview with:
Carmen J. Williams, M.D., Ph.D.
Principal Investigator
National Institute of Environmental Health

Medical Research: What is the background for this study?

Dr. Williams: G-protein coupled receptors are used by almost all cells to receive signals from the outside of the cell and transduce these signals into actions within the cell. There are hundreds of these receptors, but many of them link to a protein named Gq to transmit their signals to other cellular proteins. Gq is found in most cells, including eggs, and activating Gq protein is one way to artificially activate the egg to begin developing into an embryo, even though it is not the way sperm normally do this. In fact, if the egg is activated before the sperm arrives it prevents the sperm from binding and fusing with the egg, so fertilization cannot take place. As a result, we thought that a mechanism might be in place within eggs to prevent them from being activated prematurely by signals that could activate Gq by triggering G-protein coupled receptors. RGS2 was a good candidate for this function because it binds to Gq in a way that prevents Gq from transmitting signals to other cellular proteins.

Medical Research: What are the main findings?

Dr. Williams: We found that RGS2 is highly expressed in immature mouse oocytes at the RNA level.  This RNA is not translated into protein, however, until immediately before ovulation when the immature oocytes mature into fertilizable eggs. To determine the function of RGS2 we used RNA interference to deplete the RGS2 protein from mature eggs.  These RGS2-depleted eggs could be fertilized by sperm, which induced normal calcium signals in the eggs..  However, when we removed the outer coat of the egg with an acidic solution prior to fertilizing the eggs, we found that the eggs began releasing calcium and developing into early embryos in the absence of sperm.  It turned out that the acid exposure, which can activate Gq signaling, was inducing the calcium responses in eggs that lack RGS2. We also found that the neurotransmitter acetylcholine, which activates Gq signaling, caused calcium release and premature development in RGS2-depleted eggs. From these studies we concluded that RGS2 prevents premature calcium release in eggs by inhibiting G-protein coupled receptor signaling via Gq.

To determine if RGS2 functions in vivo, we obtained mice in which RGS2 had been genetically knocked out.  These mice produce significantly smaller litters than their wild type counterparts.  Importantly, eggs retrieved from Rgs2 knockout mice underwent premature calcium release, which changes the extracellular coat surrounding the egg to be more difficult for sperm to penetrate. Our results demonstrate that in eggs, RGS2 acts to suppress calcium release prior to fertilization and in this way keeps the egg fertilizable by sperm for a longer period of time after ovulation.

Medical Research: What should clinicians and patients take away from your report?

Dr. Williams: The most important take-home message is that proteins like RGS2 that are involved in regulating how the brain and heart function can also be important in regulating fertility. As a result, therapies that are developed for treating diverse medical problems such as anxiety and hypertension can also affect reproductive health. This should be kept in mind when considering the risks and benefits of specific medical treatments, particularly in reproductive age women.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Williams: We would like to determine if there are additional Gq-linked receptors expressed in the egg that might be stimulated to cause premature calcium release. Doing so would help identify drugs or other compounds that might interfere with egg fertilizability. It would also be very useful to determine how oocytes suppress translation of very highly expressed RNAs until maturation, when the proteins are needed for specific functions in the mature egg. Finally, because premature egg activation is associated with infertility and development of ovarian teratomas, it might also be useful to determine if any of the known polymorphisms in the RGS2 gene in humans are associated with these medical conditions.


Development. 2015 Jul 9. pii: dev.121707. [Epub ahead of print]

Regulator of G-protein signaling 2 (RGS2) suppresses premature calcium release in mouse eggs.

Bernhardt ML1, Lowther KM2, Padilla-Banks E1, McDonough CE1, Lee KN3, Evsikov AV4, Uliasz TF2, Chidiac P3, Williams CJ5, Mehlmann LM
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Carmen J. Williams, M.D., Ph.D. (2015). Protein Link Between Brain/Heart Function and Fertility 

Last Updated on July 29, 2015 by Marie Benz MD FAAD