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Pitt Neuroscientists Uncover Mechanism For Neuron Death, Counter Long-Held,,Assumptions About This Process

PITTSBURGH, Sept. 4 -- An influx of calcium specifically into mitochondria appears to trigger the death of neurons exposed to glutamate, a neurotransmitter that proves toxic when it's overproduced in traumatic brain injury and stroke. This research finding, presented by University of Pittsburgh investigators in the September issue of Nature Neuroscience, derails a long-held assumption that high concentrations of calcium within a cell's cytoplasm - and not in the mitochondria -- causes cells to die.

"In our research, we found that neurons can accumulate high amounts of calcium inside the cytoplasm without breaking down. It's only when large amounts of calcium flow into mitochondria that neurons die," said Ian Reynolds, Ph.D., associate professor of pharmacology at the University of Pittsburgh School Medicine.

"This information clearly shows that we should consider designing drugs to target mitochondria to prevent or intervene in glutamate-induced neuronal damage," said Dr. Reynolds. Specific calcium channels on the surface of mitochrondria may prove one important target for drug design, he added.

As with all living cells, a neuron consists of a cell membrane enclosing fluid cytoplasm. Within the cytoplasm are intracellular organelles, including mitochondria. Mitochondria are kidney-shaped organelles that have their own DNA and which produce energy for cells to function.

Glutamate works by binding to receptors on the surface of a neuron. This binding activates an influx of calcium that triggers the neuron to release additional glutamate, which stimulates other neurons, resulting in neurotransmission. Sometimes, however, injured or diseased nerves release too much glutamate. Excess glutamate over-stimulates neurons. The resultant neurotoxicity causes cell death.

Traditionally, neuroscientists have thought that too much calcium would perturb calcium-sensitive enzymes within the cytoplasm. Th
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Contact: Lauren Ward
wardle@msx.upmc.edu
(412) 624-2607
University of Pittsburgh Medical Center
4-Sep-1998


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