Submitted on March 13, 2008
Revised on April 15, 2008
Accepted on April 29, 2008
REGULATION OF THE VOLTAGE-GATED K+ CHANNELS KCNQ2/3 AND 3/5 BY SERUM AND GLUCOCORTICOID-REGULATED KINASE-1
Friderike Schuetz1, Sharad Kumar, Philip Poronnik PhD1, and David J. Adams1*
1 University of Queensland
* To whom correspondence should be addressed. E-mail: dadams{at}uq.edu.au.
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 <I>Xenopus</I> oocytes. SGK-1 significantly up regulated the K+ current amplitude 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 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, these results demonstrate a potential mechanism for the regulation of KCNQ2/3 and 3/5 channels by SGK-1 regulating the activity of the ubiquitin ligase Nedd4-2.
