Scientists identify a key to body's use of free calcium

January 23, 2014

Scientists at Johns Hopkins report they have figured out a key step in how "free" calcium—the kind not contained in bones—is managed in the body, a finding that could aid in the development of new treatments for a variety of neurological disorders that include Parkinson's disease.

Appearing online this week in Nature Chemical Biology, the researchers describe their use of tiny "lights" and chemical "leashes" to unveil how calcium is controlled.

Electrical signals carried by free-floating calcium ions are "wildly important to keeping the second-by-second functions of the body going," says David Yue, M.D., Ph.D., professor of biomedical engineering and neuroscience at The Johns Hopkins University.

Yue, who led the research team of graduate students Philemon Yang and Manu Ben Johny, explains that large proteins called are the gatekeepers that determine when calcium enters cells. Embedded in cell membranes, these channels open and shut to regulate calcium flow into the cell. When calcium goes into cells, it sets off a cascade of vital activity, but just the right amount of calcium must enter—otherwise, problems arise.

To achieve this balance, two chemical regulators bind to calcium channels as a brake and accelerator for calcium entry. Calmodulin, one type of calcium channel-binding protein, stops calcium from flowing through, while other proteins, known as calcium- Yue, who led the research team of graduate students Philemon Yang and Manu Ben Johny, explains that large proteins called calcium channels are the gatekeepers that determine when calcium enters cells.

Embedded in cell membranes, these channels open and shut to regulate calcium flow into the cell. When calcium goes into cells, it sets off a cascade of vital activity, but just the right amount of calcium must enter—otherwise, problems arise. To achieve this balance, two chemical regulators bind to calcium channels as a brake and accelerator for calcium entry. Calmodulin, one type of calcium channel-binding protein, stops calcium from flowing through, while other proteins, known as calcium-binding proteins, accelerate calcium entry.

In their research, Yue and his colleagues examined specific calcium channels embedded in the membranes of nerve cells in the brain to see how and CaBP4, a particular calcium-binding protein, latch onto the channels.

They rigged the odds in favor of calmodulin binding by genetically engineering calcium channels that were tethered to calmodulin by a short, flexible strand of amino acids. But to their surprise, Yue says, calcium-binding proteins stuck to the calcium channels at the same time, suggesting that each regulator has its own parking space on the channel, whereas previous theories suggested a single space.

To further examine the relationships among these regulators of calcium, the scientists used markers that glow in different colors and attached them to calcium channels, calmodulin and CaBP4. When two molecules locked together, the color changed. By measuring color changes, the researchers could then tell which molecules bound to each other.

In their research, Yue and his colleagues examined specific calcium channels embedded in the membranes of nerve cells in the brain to see how calmodulin and CaBP4, a particular calcium-binding protein, latch onto the channels.

They rigged the odds in favor of calmodulin binding by genetically engineering calcium channels that were tethered to calmodulin by a short, flexible strand of amino acids. But to their surprise, Yue says, calcium-binding proteins stuck to the calcium channels at the same time, suggesting that each regulator has its own parking space on the channel, whereas previous theories suggested a single space.

To further examine the relationships among these regulators of calcium, the scientists used markers that glow in different colors and attached them to calcium channels, calmodulin and CaBP4. When two molecules locked together, the color changed. By measuring color changes, the researchers could then tell which molecules bound to each other.

"Our experiments established that calmodulin and calcium-binding proteins work by binding to distinct parts of the calcium channel," Yue says. "More generally, we have been able to investigate how large molecules such as these function in living cells."

The "live light show" permitted by the use of light markers should help scientists develop new drugs that target calcium channels, Yue adds. Some such drugs already exist, including that lower blood pressure by targeting a particular kind of calcium channel found in blood vessels.

Blocking calcium channels might help with other diseases, too, Yue says. For example, researchers have found that an overload of calcium in certain parts of the brain may drive some neurodegenerative diseases, such as Parkinson's. Blocking the calcium channels found in those trouble spots—the kind of channels in Yue's study—could be a way to fight the debilitating brain disease.

Explore further: Like eavesdropping at a party

More information: dx.doi.org/10.1038/nchembio.1436

Related Stories

Like eavesdropping at a party

July 31, 2008

Cells rely on calcium as a universal means of communication. For example, a sudden rush of calcium can trigger nerve cells to convey thoughts in the brain or cause a heart cell to beat. A longstanding mystery has been how ...

Understanding night blindness and calcium

April 1, 2010

Congenital stationary night blindness, an inherited condition that affects one's ability to see in the dark, is caused by a mutation in a calcium channel protein that shuttles calcium into and out of cells. Now, researchers ...

Recommended for you

Findings illuminate animal evolution in protein function

July 27, 2015

Virginia Commonwealth University and University of Richmond researchers recently teamed up to explore the inner workings of cells and shed light on the 400–600 million years of evolution between humans and early animals ...

New polymer able to store energy at higher temperatures

July 30, 2015

(Phys.org)—A team of researchers at the Pennsylvania State University has created a new polymer that is able to store energy at higher temperatures than conventional polymers without breaking down. In their paper published ...

How to look for a few good catalysts

July 30, 2015

Two key physical phenomena take place at the surfaces of materials: catalysis and wetting. A catalyst enhances the rate of chemical reactions; wetting refers to how liquids spread across a surface.

Yarn from slaughterhouse waste

July 29, 2015

ETH researchers have developed a yarn from ordinary gelatine that has good qualities similar to those of merino wool fibers. Now they are working on making the yarn even more water resistant.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.