Redox Regulation of Protein Function via Cysteine S-Nitrosylation and Its Relevance to Neurodegenerative Diseases

Figure 2

Nitric oxide signaling in neuroprotection and neurodegeneration. Synaptic activity results in NMDAR channel openings, allowing Ca²⁺ entry that can activate nNOS to generate NO in neurons. Under physiological conditions, low levels of NO are produced in neurons by synaptic activity to activate neuroprotective signaling pathways involving cGMP-CGKI or S-nitrosylation of several critical proteins (NMDARs, Gospel, etc.). Under pathological conditions, excessive Ca²⁺ enters primarily through extrasynaptic NMDARs, generating large concentrations of NO. The nitrosative stress thus generated contributes to synaptic damage and neuronal loss, in part by fostering aberrant protein S-nitrosylation. Various cellular processes, including mitochondrial dynamics, protein folding, lipid metabolism, protein degradation, and signal transduction pathways can be perturbed by aberrant protein S-nitrosylation. Compromise in one or several of these cell processes can contribute to neurodegeneration. It should be noted, however, that a number of additional pathways, not related to NO, that are triggered by synaptic activity can also contribute to neuroprotection, while a number of pathways affected by extrasynaptic NMDAR activity appear to be involved in neuronal cell injury and death [99].