REGULATION OF THE VOLTAGE-GATED K+ CHANNELS KCNQ2/3 AND KCNQ3/5 BY SERUM AND GLUCOCORTICOID-REGULATED KINASE-1

Voltage-gated KCNQ2/3 and KCNQ3/5 K+ channels regulate neuronal excitability. We have recently shown that KCNQ2/3 and 3/5 channels are regulated by the ubiquitin ligase, Nedd4-2. The serum and glucocorticoid-induced kinase-1 (SGK-1) plays an important role in the regulation of epithelial ion transport. SGK-1 phosphorylation of Nedd4-2 decreases the ability of Nedd4-2 to ubiquitinate the epithelial sodium channel (ENaC) which increases the abundance of channel protein in the cell membrane. In this study, we investigated the mechanism(s) of SGK-1 regulation of M-type KCNQ channels expressed in Xenopus oocytes. SGK-1 significantly up-regulated the K+ current amplitudes of KCNQ2/3 ~1.4 fold and KCNQ3/5 ~1.7 fold whereas the kinase dead SGK-1 mutant had no effect. The cell surface levels of KCNQ2-HA/3 were also increased by SGK-1. Deletion of the KCNQ3 C-terminal in the presence of SGK-1 did not affect the K+ current amplitude of KCNQ2/3/5-mediated currents. Co-expression of Nedd4-2 and SGK-1 with either KCNQ2/3 or 3/5 did not significantly alter the current amplitudes. Only the Nedd4-2-mutant [S448A] exhibited a significant down-regulation of the KCNQ2/3/5 K+ current amplitudes. Taken together, thes