Hawaii research Two Hawaii researchers and mainland colleagues have made discoveries about how animal cells work that may lead to treatments for stroke, heart attacks and many other disorders and diseases.
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Disease-fighting clout may
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all cells use chemical e-mailBy Helen Altonn
Star-BulletinFindings of Drs. Andrea Fleig and Reinhold Penner of the Queen's Medical Center and University of Hawaii's John A. Burns School of Medicine and their associates were reported in two articles in last week's issue of the journal Nature.
In a significant scientific advance, the researchers described the regulatory mechanisms for two members of a new family of ion channels found in cells of the blood, blood vessels, liver, kidney and the immune system.
Scientists have long known that the nerves of the body act much like electrical wiring. But now they are learning that many other cells -- and perhaps all cells -- have similar electrical communication systems using charged chemicals called ions.
These so-called "non-excitable cells" don't always have their circuitry open as nerves do. Finding out when, why and how these cells communicate holds huge potential for understanding how body processes can go awry -- and result in disease.
Ion channels are proteins that form tiny pores, like doorways or tunnels, into cellular membranes. They control the entrance and exit into the body's cells of such substances as sodium, potassium and calcium. The calcium level is tightly controlled, except when the cell wants to do something, Penner said.
Understanding how these channels function may lead to new therapies for diseases of the blood, kidney, liver, arteries and immune system, as well as better ways to reduce cell damage from stroke, heart attacks and aging, Fleig and Penner said in an interview at their Queen's research center.
They are negotiating with several companies regarding development and screening of drugs, Penner said.
Fleig dubbed one channel MagNuM, for magnesium-nucleotide-regulated metal currents."We like to promote Hawaii in our research, and Magnum is an outstanding word used because of the TV show ('Magnum, P.I.')," she said. She said she watched the show often when she returned to her home in Germany after getting a doctorate degree in Hawaii. "I was so homesick for Hawaii."
Penner said Nature's reviewers commented that it was "a very cutesy name."
Although the ion channels, labeled LTRPC2 and LTRPC7, belong to the same family, they are "miles apart" in functions and mechanisms, Penner noted.
LTRPC7 is in every cell of the body, and cells die if they do not have it, said Fleig, senior author for one paper describing results of work in her Laboratory of Cell and Molecular Signaling at the Queen's Center for Biomedical Research.
Penner, center director, also was a prominent research participant. Both are world leaders in techniques to study cellular function. Penner worked at the Max Planck Institute for Biophysical Chemistry in Germany with Erwin Neher, 1991 Nobel Prize winner in physiology and medicine.
Fleig, whose lab is focusing on cellular calcium, said, "So many processes in the body are regulated through calcium, and the body cannot produce calcium itself. It has to come from outside."
She said every cell in the body has a certain task, and calcium is a way for a cell to communicate with other cells in the same organ, like the brain or heart. Calcium also is used to interpret signals from other cells and give an appropriate response, she said.
"The whole thing revolves around ion calcium, also called the 'second messenger.'"
He said the researchers have yet to fully understand the two ion channels that their papers are about.
One is operated by a molecule, ADP-ribose, that was considered useless, he said. "Now we know the molecule has function, and we have to learn under what conditions does it come into play in the cellular system."
Penner said they found the ADP-ribose channels in cells of the immune system and of the pancreas, which is important for diabetes because it is involved with insulin release.
The findings suggest ADP-ribose is able to control entry of sodium and calcium into cells with LTRPC2 channels, the researchers said.
This is potentially significant because ADP-ribose is created in large amounts by the same processes that produce free radicals and reactive oxygen species, which are implicated in cell damage occurring with aging, stroke and heart attacks.
The LTRPC7 ion channel appears to be controlled by the molecule adenosine triphosphate (ATP), which is fuel for all living cells, the scientists said.
"This is the very first ion channel found to be absolutely essential for self-survival," Penner said. "If that channel is knocked out, either experimentally or by mutation because of gene defect, that's it, the cells will die."
Cells are like balloons, Fleig said, with lipid membranes that "keep chaos out" by letting only specific signals enter the cell.
Too much or too little calcium will cause a cell to die, resulting in diseases, the researchers said.
"For example," Penner said, "we know Alzheimer's is caused by things that change the regulation of cells. So the cell really needs to keep calcium under tight control."
The cell uses ATP, produced by little fuel stations in every cell, to pump out excess calcium, the scientists said.
The ATP normally keeps everything in the cell at the right concentration, Penner said, but a cell under stress uses more ATP. The ion channels open to let new calcium enter and drive ATP production with sugar and oxygen. Then, the cells return to normal working level, and the channels close, he explained.
But if a person has a stroke or heart attack, blood flow is interrupted and oxygen is depleted, he pointed out. The cells use up the ATP, and there is no fuel to pump out the calcium.
"So it's a vicious circle. The ATP levels drop, calcium rushes in, the cell uses more ATP to get rid of the calcium, but it cannot do this because there is no ATP production. So this mechanism, which normally really helps you, can become really bad if you cannot produce ATP.
"That is the reason why we think this becomes enormously important for stroke treatments. ... We know cells eventually will be able to produce more ATP if we supply them with oxygen, but we have a short window of opportunity to actually treat a stroke."
If this problem can be solved, Penner said, "We may be able to prolong the therapeutic window quite significantly."
Excess calcium also enters cells and damages tissue when patients with diabetes receive too much insulin or oral medication, which reduces sugar to the cells, the researchers said.
Medications to block the LTRPC7 ion channel might reduce tissue damage from stroke, heart attacks and insulin shock, they said.