Requirement for cGMP in nerve cell death caused by glutathione depletion.
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.
Li
Y
Y
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Maher
P
P
Schubert
D
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D002540:Cerebral Cortex / Q000166:cytology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000633:toxicity; D005978:Glutathione / Q000172:deficiency*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction
D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D018698:Glutamic Acid; D019328:Buthionine Sulfoximine; D002248:Carbon Monoxide; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D005978:Glutathione; D006152:Cyclic GMP; D002118:Calcium