Sci. Aging Knowl. Environ., 11 February 2004
Vol. 2004, Issue 6, p. nf17
[DOI: 10.1126/sageke.2004.6.nf17]


Cell Death, Start to Finish

Nitric oxide and zinc cooperate to demolish overexcited neurons

R. John Davenport

A panorama gives a wide view that a series of snapshots only suggests, and a new study provides such a perspective on how two signaling molecules kill neurons. The work brings into focus the roles of nitric oxide (NO) and zinc in strangling overexcited brain cells. It might help researchers in their efforts to prevent brain damage associated with several age-related conditions.

Through the process known as apoptosis, organisms can direct unneeded or potentially cancerous cells to self-destruct--but such tactics can deplete irreplaceable tissue. For instance, concentrations of the neurotransmitter glutamate rise in Alzheimer's disease and stroke, in part because breaks in energy supply hamper recycling of the compound; neurons off themselves in response. Researchers have connected zinc and NO to such conditions. For example, blocking NO production or depleting zinc reduces stroke damage. Both molecules prompt apoptosis, and scientists had described many of the steps involved. But no one had knitted together all of the pieces in a single type of cell.

To tackle that challenge, neurodegeneration researcher Stuart Lipton of the Burnham Institute in La Jolla, California, and colleagues exposed cultured rat neurons to NO. Using dyes that glow when they stick to zinc, the scientists found that the metal escapes from protein molecules after NO or glutamate treatment. Because glutamate boosts NO production, the result suggests that NO spurs zinc release in response to glutamate.

Additional experiments revealed that after its liberation, zinc crippled mitochondria--cellular power stations. In addition, the energy factories swelled, churned out reactive oxygen species (ROS), and released cytochrome c, all factors that promote apoptosis.

NO and zinc elicit other cellular changes as well. Studies in nonbrain cells have suggested that NO kills cells by activating a protein called p38. The team next found that NO-treated neurons switched on p38. Moreover, blocking zinc release, preserving mitochondrial function, or quenching ROS kept p38 quiet. Further experiments showed that upon provocation by NO, p38 activates cell membrane proteins that pump potassium. As a result, internal potassium amounts plummet, causing the cells to shrink--an event that hastens their demise. The work links each of the steps in the pathway--glutamate exposure, NO rise, zinc release, mitochondria malfunction, p38 arousal, and potassium-channel opening--says Lipton.

"The pathway is very complicated, and they explore it in a rational, step-by-step way," says NO biologist Jonathan Stamler of Duke University in Durham, North Carolina. "Each individual link may have been shown in different systems, but in neurons, none of this was clear in terms of the connectivity between the parts." Researchers had previously described a similar pathway in response to a poisonous oxidant rather than to NO, says pharmacologist Ian Reynolds of the University of Pittsburgh in Pennsylvania, so the new work represents "a refinement." Lipton says that NO is more relevant than the poison is to neurodegenerative disease. Clarifying some details of the process will require further experiments, says Stamler, but ideas that come out of this wide-angle view could point researchers to new landmarks for keeping traumatized brains as healthy as possible.

February 11, 2004
  1. E. Bossy-Wetzel, Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels. Neuron 3, 351-365 (2004). [Abstract] [Full Text]
  2. C. J. Chang, J. Jaworski, E. M. Nolan, M. Sheng, S. J. Lippard, A tautomeric zinc sensor for ratiometric fluorescence imaging: Application to nitric oxide-induced release of intracellular zinc. Proc. Natl. Acad. Sci. U.S.A., 20 January 2004 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Cell Death, Start to Finish. Sci. Aging Knowl. Environ. 2004 (6), nf17 (2004).

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