title: Regulation of the voltage-gated K(+) channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1.
abstract: The voltage-gated KCNQ2/3 and KCNQ3/5 K(+) channels regulate neuronal excitability. We recently showed that KCNQ2/3 and KCNQ3/5 channels are regulated by the ubiquitin ligase Nedd4-2. Serum- and glucocorticoid-regulated kinase-1 (SGK-1) plays an important role in regulation of epithelial ion transport. SGK-1 phosphorylation of Nedd4-2 decreases the ability of Nedd4-2 to ubiquitinate the epithelial Na(+) channel, 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 upregulated the K(+) current amplitudes of KCNQ2/3 and KCNQ3/5 channels approximately 1.4- and approximately 1.7-fold, respectively, whereas the kinase-inactive SGK-1 mutant had no effect. The cell surface levels of KCNQ2-hemagglutinin/3 were also increased by SGK-1. Deletion of the KCNQ3 channel COOH terminus in the presence of SGK-1 did not affect the K(+) current amplitude of KCNQ2/3/5-mediated currents. Coexpression of Nedd4-2 and SGK-1 with KCNQ2/3 or KCNQ3/5 channels did not significantly alter K(+) current amplitudes. Only the Nedd4-2 mutant (S448A)Nedd4-2 exhibited a significant downregulation of the KCNQ2/3/5 K(+) current amplitudes. Taken together, these results demonstrate a potential mechanism for regulation of KCNQ2/3 and KCNQ3/5 channels by SGK-1 regulation of the activity of the ubiquitin ligase Nedd4-2.
authors.affiliation: School of Biomedical Sciences and Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Friderike
authors.initials: F
authors.lastname: Schuetz
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
authors.forename: Philip
authors.initials: P
authors.lastname: Poronnik
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D015536:Down-Regulation; D056827:Endosomal Sorting Complexes Required for Transport; D005260:Female; D017874:Immediate-Early Proteins / Q000502:physiology*; D015640:Ion Channel Gating; D051656:KCNQ Potassium Channels / Q000502:physiology*; D051658:KCNQ2 Potassium Channel / Q000502:physiology*; D051659:KCNQ3 Potassium Channel / Q000502:physiology*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D044967:Serum; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D029867:Xenopus Proteins; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; D017874:Immediate-Early Proteins; D051656:KCNQ Potassium Channels; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C496915:Kcnq2 protein, rat; C496918:Kcnq3 protein, rat; C501028:Kcnq5 protein, rat; C000618479:NEDD4L protein, rat; C000618482:Nedd4 protein, Xenopus; C000618484:Nedd4 protein, rat; C000618460:nedd4l protein, Xenopus