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© The Rockefeller University Press, 0021-9525/1997//1317 $5.00
The Journal of Cell Biology, Volume 139, Number 5, , 1997 1317-1324

Requirement for cGMP in Nerve Cell Death Caused by Glutathione Depletion

Yonghong Li^*, Pamela Maher, and David Schubert^*

^* Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037; and Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

Glutathione depletion occurs in several forms of apoptosis and is associated with Parkinson's disease and HIV toxicity. The neurotransmitter glutamate kills immature cortical neurons and a hippocampal nerve cell line via an oxidative pathway associated with glutathione depletion. It is shown here that soluble guanylyl cyclase (sGC) activity is required for nerve cell death caused by glutathione depletion. Inhibitors of sGC block glutamate toxicity and a cGMP analogue potentiates cell death. Glutamate also induces an elevation of cGMP that occurs late in the cell death pathway. The resultant cGMP modulates the increase in intracellular calcium that precedes cell death because sGC inhibitors prevent calcium elevation and the cGMP analogue potentiates the increase in intracellular calcium. These results suggest that the final pathway of glutamate induced nerve cell death is through a cGMP-modulated calcium channel.

Address all correspondence to David Schubert, Cellular Neurobiology Lab, The Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037. Tel.: (619) 453-4100, ext. 1562. Fax: (619) 535-9062.

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