Upregulation of HERG channels by the serum and glucocorticoid inducible kinase isoform SGK3.
Human ether-a-go-go (HERG) channels participate in the repolarization of the cardiac action potential. Loss of function mutations of HERG lead to delayed cardiac repolarization reflected by prolonged QT interval. HERG channels are regulated through a signaling cascade involving phosphatidylinositol 3 (PI3) kinase. Downstream targets of PI3 kinase include the serum and glucocorticoid inducible kinase (SGK) and protein kinase B (PKB) isoforms. The present study has been performed to explore whether SGK1 and SGK3 participate in the regulation of HERG channel activity. HERG was expressed in Xenopus oocytes with or without additional expression of SGK1 or SGK3. Chemiluminescence was employed to determine HERG plasma membrane protein abundance. Coexpression of SGK3 but not of SGK1 in Xenopus oocytes resulted in an increase of steady state current (I(HERG)) and enhanced cell membrane protein abundance without affecting gating kinetics of the channel. Replacement of serine by alanine at the two SGK consensus sites decreased I(HERG) but neither mutation abolished the stimulating effect of SGK3. In conclusion, SGK3 participates in the regulation of HERG by increasing HERG protein abundance in the plasma membrane and may thus modify the duration of the cardiac action potential.
Maier
Gottlieb
G
Department of Physiology, University of Tübingen, Tübingen, Germany.
Palmada
Monica
M
Rajamanickam
Jeyaganesh
J
Shumilina
Ekaterina
E
Böhmer
Christoph
C
Lang
Florian
F
D000200:Action Potentials; D019943:Amino Acid Substitution; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008163:Luminescent Measurements; D009154:Mutation; D009865:Oocytes; D020033:Protein Isoforms / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D051638:Ether-A-Go-Go Potassium Channels; D017874:Immediate-Early Proteins; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases