FIG. 2.

NO can both protect and sensitize cells to excitotoxic cell death through a mitochondrial pathway. (A) NO plays a key role in excitotoxic pathways mediated by NMDA Ca²⁺ channels. Under normal physiologic conditions, NO (after converting to NO⁺) S-nitrosylates NMDA receptors, blocks Ca²⁺ influx, and promotes cell survival. (B) When mtNOS is responsible for the majority of NOS activity (as is the case in immature neurons), Ca²⁺ enters mitochondria and stimulates NO production by mtNOS. NO inhibits the respiratory chain, which reduces the mitochondrial membrane potential, collapses the ion gradient, and decreases entry of Ca²⁺ into the mitochondria. Decreased Ca²⁺ influx causes a decrease in mtNOS activity and NO production, promoting cell survival. (C) When cytosolic nNOS is the primary producer of NO (as is the case in mature neurons), Ca²⁺ entry through overactive NMDA channels stimulates nNOS, and NO can then enter the mitochondria and directly inhibit complex IV (cytochrome c oxidase; COX) of the respiratory chain, which leads to a block of ATP production and eventual cell death due to energetic failure. In contrast to pathway B, no feedback loop is present to protect the cell from damage. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).