The stimulation of cell proliferation by insulin like growth factor IGF-1 has previously been shown to depend on activation of voltage gated K(+) channels. The signaling involved in activation of voltage gated K(+) channel Kv1.3 includes the phosphatidylinositol-3 (PI3) protein kinase, 3-phosphoinositide dependent protein kinase PDK1 and the serum and glucocorticoid inducible kinase SGK1. However, nothing is known about mechanisms mediating the stimulation of Kv1.3 by SGK1. Most recently, SGK1 has been shown to phosphorylate and thus inactivate the ubiquitin ligase Nedd4-2. The present study has been performed to explore whether the regulation of Kv1.3 involves Nedd4-2. To this end Kv1.3 has been expressed in Xenopus oocytes with or without coexpression of Nedd4-2 and/or constitutively active (S422D)SGK1. In oocytes expressing Kv1.3 but not in water injected oocytes, depolarization from a holding potential of -80 mV to +20 mV triggers rapidly inactivating currents typical for Kv1.3. Coexpression of Nedd4-2 decreases, coexpression of (S422D)SGK1 enhances the currents significantly. The effects of either Nedd4-2 or of SGK1 are abrogated by destruction of the respective catalytic subunits ((C938S)Nedd4-2 or (K127N)SGK1). Further experiments revealed that wild type SGK1 and SGK3 and to a lesser extent SGK2 are similarly effective in stimulating Kv1.3 in both, presence and absence of Nedd4-2. It is concluded that Kv1.3 is downregulated by Nedd4-2 and stimulates by SGK1, SGK2, and SGK3. The data thus disclose a novel mechanism of Kv1.3 channel regulation.