REQUIREMENT FOR CGMP IN NERVE-CELL DEATH CAUSED BY GLUTATHIONE DEPLETION

Glutathione depletion occurs in several forms of apoptosis and is asso ciated with Parkinson's disease and HIV toxicity. The neurotransmitter glutamate kills immature cortical neurons and a hippocampal nerve cel l line via an oxidative pathway associated with glutathione depletion. It is shown here that soluble guanylyl cyclase (sGC) activity is requ ired for nerve cell death caused by glutathione depletion. Inhibitors of sGC block glutamate toxicity and a cGMP analogue potentiates cell d eath. Glutamate also induces an elevation of cGMP that occurs late in the cell death pathway. The resultant cGMP modulates the increase in i ntracellular calcium that precedes cell death because sGC inhibitors p revent calcium elevation and the cGMP analogue potentiates the increas e in intracellular calcium. These results suggest that the final pathw ay of glutamate induced nerve cell death is through a cGMP-modulated c alcium channel.