Protein S-Nitrosylation in Neuronal Development

Reactive nitrogen species (RNS) such as nitric oxide (NO) act as signaling molecules that mediate both physiological and pathological processes. Recent evidence in biological systems has shown the ubiquitous nature of a redox-mediated post-translational modification of specific cysteine thiols (or more properly, thiolate anion S-) by NO, most likely in the form of a nitrosonium cation intermediate (NO+). This nitrosation reaction is now termed protein S-nitrosylation and represents a key mechanism for the biological actions of NO. Like other post-translational modifications, S-nitrosylation can affect ion channel activity, enzymatic function, protein conformation, protein-protein interactions, and protein trafficking and localization. In the nervous system, S-nitrosylation was first discovered on the NMDA type of glutamate receptor (NMDAR) and occurs on many proteins affecting neuronal survival, synaptic function, neurogenesis, and other aspects of neuronal development. This chapter provides an overview of the molecular and cellular mechanisms by which RNS regulate neuronal differentiation via S-nitrosylation of proteins such as histone deacetylation enzyme HDAC2 and transcription factor MEF2. Dysregulation of the S-nitrosylation signaling network can impair normal brain development/neurogenesis as well as adult neurogenesis, contributing to neurodevelopmental and neurodegenerative conditions. Further investigation into the mechanism of S-nitrosylation-regulated neuronal differentiation should elucidate pathogenic features of these disorders.