Regulation of channels by the serum and glucocorticoid-inducible kinase - implications for transport, excitability and cell proliferation.
The serum and glucocorticoid-inducible kinase SGK1 stimulates the Na+ channels ENaC and SCN5A, the K+ channels ROMK1, Kv1.3, and KCNE1/KCNQ1, the cation conductance induced by 4F2/LAT1 and the chloride conductance induced by CFTR. The isoforms SGK2 and SGK3 have similarly been shown to regulate ENaC, SCN5A, Kv1.3 and KCNE1/KCNQ1. The kinases regulate channel abundance in the plasma membrane in part by inhibition of the ubiquitin ligase Nedd4-2 and in part by interaction with trafficking molecules such as the Na+/H+ exchanger regulating factor NHERF2. An in vivo role of SGK1 mediated ENaC channel regulation in renal salt excretion and blood pressure control is documented by the impaired ability of SGK1 knockout mice to adequately reduce renal Na+ output and maintain blood pressure during dietary salt restriction and by enhanced blood pressure in individuals carrying certain polymorphisms in the SGK1 gene. The in vivo physiological significance of SGK dependent regulation of the other channels remains to be shown even though circumstantial evidence points to involvement in the regulation of epithelial transport, cell volume, cell proliferation, cardiac action potential and neuroexcitability. There is little doubt that further channels will be identified which are modulated by the SGKs and that further in vivo physiological functions will be defined where channel regulation by the SGKs plays a critical role.
Lang
Florian
F
Department of Physiology, University of Tuebingen, Germany. florian.lang@uni-tuebingen.de
Henke
Guido
G
Embark
Hamdy M
HM
Waldegger
Siegfried
S
Palmada
Monica
M
Böhmer
Chtristoph
C
Vallon
Volker
V
D000818:Animals; D001692:Biological Transport; D002455:Cell Division / Q000502:physiology; D018118:Chloride Channels / Q000502:physiology*; D004789:Enzyme Activation; D004790:Enzyme Induction / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D017874:Immediate-Early Proteins; D008954:Models, Biological; D009687:Nuclear Proteins; D015221:Potassium Channels / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000502:physiology*; D000099184:Serum-Glucocorticoid Regulated Kinases
D018118:Chloride Channels; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D015221:Potassium Channels; D017346:Protein Serine-Threonine Kinases; D015222:Sodium Channels; D000099184:Serum-Glucocorticoid Regulated Kinases