Queen's Center for Biomedical Research Discovery Published in "Molecular Cell"

Martin Kolisek, PhD, of the QCBR performed most of the experimental work for the published research. Andreas Beck, PhD, Andrea Fleig, PhD, and Reinhold Penner, MD, PhD, were also principal researchers.

An astronomer may see a shiny, new object in the night sky and speculate about what it might be. Researchers at Queen's Center for Biomedical Research often see the equivalent of such an object, but at the molecular level. Recently, research at QCBR uncovered something interesting along the pathway to understanding ion channels and their role in major diseases. The research, which may have implications for the treatment stroke and diabetes, was published in the April 1, 2005 issue of the journal Molecular Cell, vol. 18, 61-69.

The "object" researchers saw was that the ion channel TRPM2-discovered earlier by QCBR-is opened by only one compound—ADP Ribose (ADPR)—in high concentrations. Normally, ion channels—donut-shaped pores in cell membranes—remain closed, but open when specific compounds bind to them, in this case ADPR. ADPR is found inside a cell's mitochondria. Researchers still don't know how ADPR gets out of the mitochondria or how the compound is regulated. Furthermore, TRPM2 requires unnaturally high amounts of ADPR to open. But they had some clues:

Hydrogen peroxide, which is produced by cells, releases ADPR.

Another form of ADPR-cyclic ADP Ribose (cADPR)-exists inside cells, but not in the mitochondria.

At first, the researchers speculated that maybe this molecularly circular cADPR opens the TRPM2 channel, but experiments showed that this is not the case. They then experimented with a lower concentration of ADPR and added cADPR-which opened TRPM2. The researchers discovered that cADPR increases the ion channel's sensitivity to ADPR by 500 times or more. They also discovered that hydrogen peroxide does the same thing as cADPR.

Researchers still don't know the special circumstances that open TRPM2 normally. However, when a person has a stroke, massive amounts of calcium flows through ion channels like TRPM2 and kills cells. Researchers at QCBR are therefore attempting to find compounds that will block these channels and put them into stroke models.

TRPM2 is also linked to diabetes. The insulin-releasing cells in the pancreas may use this channel to release insulin. TRPM2 may not be working properly in people with diabetes, and so QCBR researchers are also searching for compounds to open the channel appropriately for those with the disease.