Fig. 2.

Overstimulation of NMDA receptors (NMDARs) by glutamate (Glu) and glycine (Gly) induces excessive Ca²⁺ influx, activation of neuronal NO synthase (nNOS), and subsequent formation of SNO proteins. nNOS produces NO from l-arginine, and NO reacts with sulfhydryl groups to form S-nitrosylated proteins. Physiological levels of NO mediate neuroprotective effects, at least in part, by S-nitrosylating the NMDAR and caspases, thus inhibiting their activity. In contrast, we postulate that overproduction of NO can be neurotoxic via S-nitrosylation of Parkin (forming SNO-PARK), PDI (forming SNO-PDI), GAPDH, MMP-2/9, PrxII, and COX-2. S-Nitrosylated parkin and PDI contribute to neuronal cell injury by triggering accumulation of misfolded proteins. S-Nitrosylation of Drp1 (forming SNO-Drp1) causes excessive mitochondrial fragmentation in neurodegenerative conditions.