Calcium Storage, Release Mechanism Revealed

March 14, 1997

Electrically charged calcium ions are key players in the drama of cell life and death. Their movement in and out of cells can determine whether the walls of arteries squeeze shut, restricting blood flow to the brain, whether hearts beat or stop beating.

Now, for the first time, physiologists at the University of Maryland School of Medicine have booked a ringside seat at the show. Using a new technology that enabled them to visualize the organization of calcium stored deep within intact muscle and brain cells, researchers in the medical school's Center for Vascular Biology and Hypertension discovered that calcium is stored in tiny, discrete compartments. The doors to different compartments can be opened or closed by various drugs or natural chemicals produced by the body, releasing different amounts of calcium to control a broad range of physiological processes.

"These findings apply to virtually every cell in the body," said Dr. Mordecai P. Blaustein, professor and chairman of physiology at the University of Maryland School of Medicine. "This could lead to a better understanding of the physiological mechanisms underlying high blood pressure, heart failure, stroke, even aging."

He and Dr. Vera A. Golovina, research associate in physiology, report their findings in the March 14 issue of Science.

Most things cells do - contraction, secretion, reproduction, synthesis of proteins - rely on the release of the right amount of calcium at the right time and place. Calcium is stored in cells in a structure called the reticulum, a series of interconnected tubules and tiny sacs distributed throughout the cells.

Too much calcium can cause cell injury or even death. The amount of calcium in the reticulum that can get out of storage to do its work depends on the concentration of another potent chemical - sodium - between a cell's outer membrane and the nearby intracellular calcium stores. Small changes in sodium concentration can produce large changes in calcium stores. Increasing sodium increases the amount of calcium that can be released from the stores.

In a related paper published in the March 4 issue of Proceedings of the National Academy of Sciences, Blaustein and Dr. Magdalena Juhaszova, research assistant professor in physiology at the University of Maryland School of Medicine, reported finding that although all cells have at least two of three varieties of sodium pump, these varieties are found in different places in the cells. The sodium pump is the body's natural transport mechanism for moving sodium in or out of cells. One variety of sodium pump is extremely sensitive to endogenous ouabain, a ouabain-like human hormone that impairs a cell's ability to get rid of excess sodium. Ouabain is a plant product related to digitalis, long used as a heart medication. Another form of sodium pump doesn't respond to the minute amounts of this hormone found normally in the body.

Using sophisticated laboratory techniques to study smooth-muscle cells such as those in the walls of arteries, nerve cells and other brain cells known as astrocytes, the researchers pinpointed the locations of these various sodium pumps on each type of cell's outer or plasma membrane. They found that the pumps that were most sensitive to ouabain are located next to the reticulum, suggesting that these pumps probably play a special role in regulating calcium levels.

"We used to think that all sodium pumps controlled the global sodium concentration in the cell" said Blaustein. "Now we know that some sodium pumps only control the sodium concentration in the space between the plasma membrane and the reticulum, and because of that, actually help to control calcium."

In 1991, Blaustein and colleagues reported their discovery that a ouabain-like compound is found naturally in minute concentrations in blood and that it affects a cell's ability to get rid of excess sodium. Their discovery was regarded as an important new piece of the high blood-pressure puzzle.

"Now we're starting to understand the crosstalk between the sodium pumps on the plasma membrane and the calcium stores in the reticulum," said Blaustein. "This will give us new insight into the whole story of cell signaling." Blaustein and colleagues' research is supported by the National Institutes of Health.
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University of Maryland School of Medicine

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