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Release: Dec. 7, 2000

UI study suggests different forms of a protein regulate uterine contractions

IOWA CITY, Iowa -- University of Iowa researchers who study uterine contractions at a molecular level have made a finding that could provide insight into preventing pre-term contractions.

The researchers, led by Sarah K. England, Ph.D., UI assistant professor of physiology and biophysics, are investigating a protein involved in controlling uterine contractions. The so-called maxi-K channel protein forms pores, or channels, in cell membranes that allow potassium ions to flow out of cells.

"We know that when these channels are open, the uterus relaxes and when the channels are closed, the uterus contracts," England said. "But we don't know precisely how this channel is regulated during pregnancy."

During labor it is critical that the muscles of the uterus contract. However, it is equally important that those muscles remain relaxed during the preceding phases of pregnancy. To better understand the role of the maxi-K channel in controlling uterine excitability and contractility during pregnancy, the researchers studied the channel protein in mouse uterine smooth muscle at multiple stages of pregnancy.

"The channels in mice seem to be regulated in a similar way to those in humans, making the mouse a good model for studying this process," England said.

England and her colleagues found that the total amount of channel protein increased during gestation. However, the flow of potassium ions, a measure of the number of open channels, decreased. This indicated that the maxi-K channelCHANNEL proteins have somehow been modified such that the channels do not open so readily.

Previous work, in both humans and mice, has shown that this protein is normally present in uterine tissue in multiple forms (isoforms). A biological mechanism known as alternative splicing causes different forms of the protein to be made. These variants are very similar but they have different sensitivities to factors such as calcium levels and voltage, which regulate channel action.

The researchers could not directly measure the amounts of each protein isoform. Instead, they measured the levels of the genetic molecule, which encodes for each protein, at different times during pregnancy. England's team found that different amounts of the various forms are present at different times during pregnancy. The study also found that one form of the channel protein, which is less sensitive to calcium and voltage, seems to be more prevalent at the end of pregnancy. The decreased sensitivity means that the channels are more often closed than open, causing the uterine muscles to contract.

"The increased levels of this isoform toward the end of gestation would allow the uterus to contract more efficiently and allow the labor process to ensue," England said.

In addition to their on-going efforts to understand how modulation of the levels of the
maxi-K protein isoforms alters the excitability and contractility of uterine tissue, the research team also plans to investigate the role hormones associated with pregnancy play in this process.

"We hope that drugs could ultimately be designed to interact specifically with this protein to treat pre-term contractions," England said. "The goal of our research is to fully understand the regulation of this channel in uterine tissue so we can better define targets for potential drugs."

The UI study appeared in the September 8 issue of the Journal of Biological Chemistry. Nancy A. Benkusky, a research assistant in England's lab, was the lead author. The work was funded by grants from the National Institutes of Health and the National Science Foundation.

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