The Physiological Role of O-Glcnacylation in the Dopamine System

Abstract

O-GlcNAcylation is one of pivotal post-translational modifications orchestrating fundamental cellular processes, including transcription, translation, and signal transduction. It attaches O-linked N-acetylglucosamine (O-GlcNAc) to serine, threonine residues of cytoplasmic, nuclear, and mitochondrial proteins. Since both O-GlcNAcylation and phosphorylation occur at the same residues, O-GlcNAcylation can compete or interact with phosphorylation in multiple cellular functions. Interestingly, O-GlcNAcylation and two enzymes governing O-GlcNAcylation are highly abundant in the brain. There have been reports showing the role of O-GlcNAcylation in modulating neuronal and synaptic properties. In addition, functional relevance of O-GlcNAcylation in neurological diseases has recently begun to emerge. Despite these findings, our understanding about the functional significance of O-GlcNAcylation in various brain systems and disorders remains rudimentary. We show that genetic manipulation of O-GlcNAc level in the dopamine system caused structural and functional changes. Furthermore, up-and down-regulation of OGlcNAcylation were associated with the corresponding alterations of mouse behaviors that are mediated by the dopamine system. These results demonstrate that O-GlcNAcylation may play a vital role in regulating structures and functions of dopamine system.