CIC-2 participates in the regulation of neuronal excitability, chloride secretion, and cell volume. The CIC-2 sequence contains a consensus site (Ser82) for phosphorylation by the serum and glucocorticoid inducible kinase isoforms SGK1-3. Thus, the present study explored whether CIC-2 is regulated by those kinases. CIC-2 expression in Xenopus oocytes induced inwardly rectifying currents that increased upon coexpression of SGK1-3 and the related kinase PKB. The stimulatory effect was still present upon disruption of the SGK phosphorylation site. SGKs can phosphorylate the ubiquitin ligase Nedd4-2 and prevent Nedd4-2 from binding to its target. Therefore, the role of Nedd4-2 in CIC-2 modulation was investigated. CIC-2 activity decreased upon Nedd4-2 coexpression. an effect reversed by the kinases. According to chemiluminescence CIC-2 membrane abundance was enhanced by SGKs and diminished by Nedd4-2. These observations suggest that SGK1-3 and Nedd4-2 regulate CIC-2 at least in part by modulating CIC-2 abundance at the plasma membrane. (C) 2004 Elsevier Inc. All rights reserved.