The human excitatory amino acid transporter EAAT2 is the major glutamate carrier in the mammalian CNS. Defective expression of the transporter results in neuroexcitotoxicity that may contribute to neuronal disorders such as amyotrophic lateral sclerosis (ALS). The serum and glucocorticoid inducible kinase 1 (SGK1) is expressed in the brain and known to interact with the ubiquitin ligase Nedd4-2 to modulate membrane transport systems. The present study aimed to investigate whether SGK and the related protein kinase B (PKB) regulate EAAT2. Expression studies in Xenopus oocytes demonstrated that glutamate induced inward current (IGLU) was stimulated by coexpression of SGK or PKB and virtually abolished by Nedd4-2, an effect abrogated by additional coexpression of either kinase. SGKs increase the transporter maximal velocity without significantly affecting substrate affinity. Similar to glutamate induced currents, [3H] glutamate uptake and cell surface abundance of the transporter were increased by the SGK isoforms and downregulated by the ubiquitin ligase Nedd4-2. In conclusion, all three SGK isoforms and PKB increase EAAT2 activity and plasma membrane expression and thus may participate in the regulation of neuroexcitability.