Background:The glutamate transporter GLT-1 is regulated by PKC, which promotes its ubiquitination and subsequent endocytosis. Results: Phosphorylation of GLT-1 occurs at Ser-520, whereas ubiquitination is mediated by the ubiquitin ligase Nedd4-2. Conclusion: PKC-promoted endocytosis of GLT-1 requires Nedd4-2-dependent ubiquitination but not its phosphorylation. Significance: Intracellular trafficking of glutamate transporters seems to play a major role in the pathophysiology of the nervous system.