Modulation of the voltage-gated potassium channel Kv1.5 by the SGK1 protein kinase involves inhibition of channel ubiquitination.
The serum and glucocorticoid inducible kinase SGK1 is involved in dexamethasone-induced inhibition of insulin secretion by increasing voltage-gated potassium channel (Kv) activity. SGK1 upregulates the Kv1.5 channel but the precise mechanism underlying the SGK1 dependent regulation of Kv1.5 has not been defined yet. The present study explored the signal transduction processes involved. Expression studies in Xenopus oocytes revealed that SGK1 promotes channel activity by interfering with the Nedd4-2 ubiquitination pathway, irrespective of the presence of putative SGK1 phosphorylation sites on Kv1.5. Expression of the ubiquitin ligase Nedd4-2 declined Kv1.5 currents by ubiquitinating and thereby reducing Kv1.5 plasma membrane expression. Increasing concentrations of SGK1 gradually compensated the inhibiting effect of Nedd4-2 on Kv1.5. Enhanced Kv1.5 surface abundance by SGK1 reflects decreased channel internalization as indicated by Brefeldin A experiments. In conclusion, Kv1.5 upregulation by SGK1 involves inhibition of channel ubiquitination by Nedd4-2 that leads to Kv1.5 stabilization in the plasma membrane. Our results suggest that the kinase might participate in the regulation of insulin secretion in part by controlling Kv1.5 surface abundance.
Boehmer
Christoph
C
Department of Physiology I, University of Tübingen, Tübingen, Germany.
Laufer
Jörg
J
Jeyaraj
Sankarganesh
S
Klaus
Fabian
F
Lindner
Ricco
R
Lang
Florian
F
Palmada
Monica
M
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D056827:Endosomal Sorting Complexes Required for Transport; D017874:Immediate-Early Proteins / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007700:Kinetics; D051666:Kv1.5 Potassium Channel / Q000378:metabolism*; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D014981:Xenopus / Q000378:metabolism*; D029867:Xenopus Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases
D003907:Dexamethasone; D056827:Endosomal Sorting Complexes Required for Transport; D017874:Immediate-Early Proteins; D007328:Insulin; D051666:Kv1.5 Potassium Channel; D000075702:Nedd4 Ubiquitin Protein Ligases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D029867:Xenopus Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C000618482:Nedd4 protein, Xenopus; C000618460:nedd4l protein, Xenopus