Association of the serum and glucocorticoid regulated kinase (sgk1) gene with QT interval.
The serum and glucocorticoid inducible kinase (SGK1) is well known to up-regulate the renal epithelial Na(+) channel ENaC. Excessive SGK1 activity would be expected to cause renal Na(+) retention and blood pressure increase. Certain polymorphisms of the SGK1 gene (E8CC/CT;I6CC) are indeed associated with moderately enhanced blood pressure. We have recently disclosed another function of SGK1, i.e. the stimulation of the slowly activating K(+) channel KCNE1/KCNQ1. Among the functions of this channel is the repolarisation of cardiac myocytes. Accordingly, defective KCNE1 and/or KCNQ1 lead to long QT syndrome, a disorder causing fainting and sudden cardiac death. In the present study we demonstrate that coexpression of SGK1 in Xenopus oocytes increases KCNQ1/KCNE1 induced current without significantly altering voltage dependence, activation and deactivation kinetics. To test for the relevance of SGK1 in human cardiac repolarization, we analysed the ECG of monozygotic (MZ) (126 pairs) and dizygotic (DZ) (70 pairs) twin subjects and parents of DZ twins. The E8CC/CT;I6CC polymorphism was indeed significantly (p<0.025) associated with shortened age and gender corrected QT interval. No significant differences were observed in any other ECG parameter, including heart rate, P, PQ and QRS. We conclude that the regulation of KCNE1/KCNQ1 by SGK1 is similarly relevant for the repolarization of cardiac myocytes as for regulation of renal ENaC activity and blood pressure control.
Busjahn
Andreas
A
Franz Volhard Clinic, HELIOS Kliniken-Berlin and Max Delbrück Center for Molecular Medicine, Medical Faculty of the Charité, Humboldt University of Berlin, Germany.
Seebohm
Guiscard
G
Maier
Gottlieb
G
Toliat
Mohammad Reza
MR
Nürnberg
Peter
P
Aydin
Atakan
A
Luft
Friedrich C
FC
Lang
Florian
F
D000818:Animals; D015415:Biomarkers; D004562:Electrocardiography; D004563:Electrochemistry; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006339:Heart Rate / Q000235:genetics / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism*; D017874:Immediate-Early Proteins; D008297:Male; D008564:Membrane Potentials; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D015222:Sodium Channels / Q000378:metabolism; D014981:Xenopus; D000099184:Serum-Glucocorticoid Regulated Kinases
D015415:Biomarkers; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D024642:Potassium Channels, Voltage-Gated; D017346:Protein Serine-Threonine Kinases; D015222:Sodium Channels; D000099184:Serum-Glucocorticoid Regulated Kinases; C489622:KCNE1 protein, human; C502068:KCNE5 protein, human