title: The serum- and glucocorticoid-inducible kinases SGK1 and SGK3 regulate hERG channel expression via ubiquitin ligase Nedd4-2 and GTPase Rab11.
abstract: The hERG (human ether-a-go-go-related gene) encodes the α subunit of the rapidly activating delayed rectifier potassium channel (IKr). Dysfunction of hERG channels due to mutations or certain medications causes long QT syndrome, which can lead to fatal ventricular arrhythmias or sudden death. Although the abundance of hERG in the plasma membrane is a key determinant of hERG functionality, the mechanisms underlying its regulation are not well understood. In the present study, we demonstrated that overexpression of the stress-responsive serum- and glucocorticoid-inducible kinase (SGK) isoforms SGK1 and SGK3 increased the current and expression level of the membrane-localized mature proteins of hERG channels stably expressed in HEK 293 (hERG-HEK) cells. Furthermore, the synthetic glucocorticoid, dexamethasone, increased the current and abundance of mature ERG proteins in both hERG-HEK cells and neonatal cardiac myocytes through the enhancement of SGK1 but not SGK3 expression. We have previously shown that mature hERG channels are degraded by ubiquitin ligase Nedd4-2 via enhanced channel ubiquitination. Here, we showed that SGK1 or SGK3 overexpression increased Nedd4-2 phosphorylation, which is known to inhibit Nedd4-2 activity. Nonetheless, disruption of the Nedd4-2 binding site in hERG channels did not eliminate the SGK-induced increase in hERG expression. Additional disruption of Rab11 proteins led to a complete elimination of SGK-mediated increase in hERG expression. These results show that SGK enhances the expression level of mature hERG channels by inhibiting Nedd4-2 as well as by promoting Rab11-mediated hERG recycling.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Lamothe
authors.forename: Shetuan
authors.initials: S
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001665:Binding Sites; D003907:Dexamethasone / Q000494:pharmacology; D000072237:ERG1 Potassium Channel; D056827:Endosomal Sorting Complexes Required for Transport / Q000096:biosynthesis* / Q000235:genetics; D051638:Ether-A-Go-Go Potassium Channels / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D000075702:Nedd4 Ubiquitin Protein Ligases; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099193:rab11 GTP-Binding Proteins
chemical_list: D003907:Dexamethasone; D000072237:ERG1 Potassium Channel; D056827:Endosomal Sorting Complexes Required for Transport; D051638:Ether-A-Go-Go Potassium Channels; D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D020691:rab GTP-Binding Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099193:rab11 GTP-Binding Proteins; C000606913:KCNH2 protein, human; C000618479:NEDD4L protein, rat; C000618483:Nedd4 protein, human; C000618484:Nedd4 protein, rat; C000618485:Nedd4L protein, human; C403243:SGK3 protein, human
keywords: Cell Biology; Cell Surface Protein; Electrophysiology; Herg; Immunohistochemistry; Ion Channels; Membrane Proteins; Molecular Biology; Rab Proteins; Ubiquitin Ligase