Sci. Aging Knowl. Environ., 2 February 2005
Broken pump abets calcium overload after a stroke
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2005/5/nf10
Without a good bilge pump, ships can flood and sink--and so can cells. After a stroke, a cellular pump protein breaks down, allowing a deadly accumulation of calcium, new results reveal. The study uncovers a protein-eating molecule that dismantles the channel and suggests that preventing the razing might stave off stroke damage.
During a stroke, part of the brain loses its oxygen supply and the energy necessary for normal activities. For instance, brain cells can't absorb glutamate. This neurotransmitter sends signals to a neuron by switching on proteins that bring calcium into the cell. This calcium wave quickly subsides. But sustained glutamate quantities such as those caused by a stroke incite a second, prolonged flood of calcium that kills cells. Researchers don't know what triggers this deluge.
Neurons tote proteins in their membranes that discharge calcium by swapping it for sodium. In the new study, Bano and colleagues investigated whether these proteins, called Na/Ca exchangers (NCX), malfunction after a stroke. The researchers caused strokes in rats by tying off an artery that supplies blood to the brain and analyzed brain tissue. One type of NCX known as NCX3 was shorter in rats that had suffered strokes than in control animals. Next, they grew neurons in a culture dish and added glutamate to simulate the effects of a blood cutoff. NCX3 was stunted in treated cells. The findings suggest that strokes induce cells to trim the protein.
Blocking calpain, a protein-devouring molecule activated by calcium, prevented NCX3 trimming, so the team investigated whether calpain's activity influenced calcium quantities inside neurons. After a dousing with glutamate, normal neurons showed an immediate surge of calcium, followed by a second torrent 15 minutes later. Cells that manufactured a calpain-shackling protein didn't undergo the second burst. Fewer of these cells died after glutamate treatment, compared to normal cells. Replacing NCX3 with NCX2, a form that calpain doesn't clip, prevented the calcium glut and helped cells survive. Together, the results suggest that calcium accumulates after a stroke because calpain snips NCX3 into a feckless form.
Previous studies showed that calpain inhibitors prevent stroke damage in animals, says neurophysiologist Zhi-Gang Xiong of the Legacy Clinical Research and Technology Center in Portland, Oregon. The new results suggest that they work by keeping NCX3 intact and encouraging calcium dispersal, he says. He'd like to know whether crippling NCX3 exacerbates calcium buildup spurred by signals besides glutamate, such as acid accumulation (see "Acid Trip"). Neurobiologist Michael Tymianski of the University of Toronto in Canada says that scientists have known for many years that calcium bursts kill neurons, and the new work "goes a long way toward explaining the mechanism." But the researchers need to address an apparent discrepancy with other findings. Glutamate induces changes in neurons that push NCX proteins to run in reverse, pumping calcium into cells, says Tymianski. He predicts that, under those circumstances, whittling NCX3 would protect cells rather than harm them. A deeper understanding of these proteins could reveal better ways of keeping calcium tides from rising.
February 2, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150