© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A
aDepartment of Physiology I, University of Tübingen, Gmelinstrasse 5, D-72076 Tübingen, Germany
bInstitute of Pathology, University of Greifswald, Greifswald, Germany
cMRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, UK
dDepartment of Internal Medicine, University of Göttingen, Göttingen, Germany
florian.lang{at}uni-tuebingen.de
* Corresponding author. Tel.: +49-7071-297-2194; fax: +49-7071-295-618.
The serum and glucocorticoid inducible kinase SGK1 and its isoform SGK3 are both expressed in cardiac tissue. One of the functions of SGK1 is the phosphorylation and inactivation of the ubiquitin ligase Nedd4-2, which in turn could be shown to downregulate the voltage-gated Na+ channel SCN5A (hH1). The present study has been performed to test for a role of SGK1 and SGK3 in the regulation of SCN5A. To this end cRNA encoding the human Na+ channel SCN5A was injected into Xenopus laevis oocytes with or without cRNA encoding the wild-type kinases SGK1, the constitutively active kinase S422DSGK1, the inactive form K127NSGK1 or the wild-type SGK3. SCN5A currents were activated by coexpression of either wild-type SGK1 or SGK3 or the constitutively active S422DSGK1. In contrast, the inactive mutant K127NSGK1 significantly decreased the currents. Moreover, coexpression of SGK3 significantly altered SCN5A gating, i.e. it hyperpolarized the activation threshold and depolarized the prepotential required for 50% availability of the channel. Opposite shifts of gating properties were elicited by mutation of serine to alanine (S483ASCN5A and S663ASCN5A) in the SGK consensus sequences of SCN5A. The present observations disclose a role of the kinases SGK1 and SGK3 in the regulation of cardiac Na+ channels. As SGK1 is upregulated by glucocorticoids, mineralocorticoids and a variety of inflammatory mediators and both kinases are activated by insulin and IGF1, the kinases could mediate effects of those hormones and mediators on cardiac function.
KEYWORDS Arrhythmia (mechanisms); Growth factors; Hormones; Infection/inflammation; Ion channels; Membrane currents; Membrane potential; Na-channel; Protein kinases; Signal transduction
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  L. Belova, D. R. Brickley, B. Ky, S. K. Sharma, and S. D. Conzen Hsp90 Regulates the Phosphorylation and Activity of Serum- and Glucocorticoid-regulated Kinase-1 J. Biol. Chem., July 4, 2008; 283(27): 18821 - 18831. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Schuetz, S. Kumar, P. Poronnik, and D. J. Adams Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1 Am J Physiol Cell Physiol, July 1, 2008; 295(1): C73 - C80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Lang, C. Bohmer, M. Palmada, G. Seebohm, N. Strutz-Seebohm, and V. Vallon (Patho)physiological Significance of the Serum- and Glucocorticoid-Inducible Kinase Isoforms. Physiol Rev, October 1, 2006; 86(4): 1151 - 1178. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Arthur, A. Sanchez-Perez, and D. I. Cook Scoring of predicted GRK2 phosphorylation sites in Nedd4-2 Bioinformatics, September 15, 2006; 22(18): 2192 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Sorkina, M. Miranda, K. R. Dionne, B. R. Hoover, N. R. Zahniser, and A. Sorkin RNA Interference Screen Reveals an Essential Role of Nedd4-2 in Dopamine Transporter Ubiquitination and Endocytosis J. Neurosci., August 2, 2006; 26(31): 8195 - 8205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B.-e Xu, S. Stippec, P.-Y. Chu, A. Lazrak, X.-J. Li, B.-H. Lee, J. M. English, B. Ortega, C.-L. Huang, and M. H. Cobb WNK1 activates SGK1 to regulate the epithelial sodium channel PNAS, July 19, 2005; 102(29): 10315 - 10320. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Aoyama, T. Matsui, M. Novikov, J. Park, B. Hemmings, and A. Rosenzweig Serum and Glucocorticoid-Responsive Kinase-1 Regulates Cardiomyocyte Survival and Hypertrophic Response Circulation, April 5, 2005; 111(13): 1652 - 1659. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. P. Thomas, J. R. Campbell, P. J. Wright, and R. F. Husted cAMP-stimulated Na+ transport in H441 distal lung epithelial cells: role of PKA, phosphatidylinositol 3-kinase, and sgk1 Am J Physiol Lung Cell Mol Physiol, October 1, 2004; 287(4): L843 - L851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Dinudom, A. B. Fotia, R. J. Lefkowitz, J. A. Young, S. Kumar, and D. I. Cook The kinase Grk2 regulates Nedd4/Nedd4-2-dependent control of epithelial Na+ channels PNAS, August 10, 2004; 101(32): 11886 - 11890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Suzuki and R. J. Handa Regulation of Estrogen Receptor-{beta} Expression in the Female Rat Hypothalamus: Differential Effects of Dexamethasone and Estradiol Endocrinology, August 1, 2004; 145(8): 3658 - 3670. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Schniepp, K. Kohler, T. Ladewig, E. Guenther, G. Henke, M. Palmada, C. Boehmer, J. D. Rothstein, S. Broer, and F. Lang Retinal Colocalization and In Vitro Interaction of the Glutamate Receptor EAAT3 and the Serum- and Glucocorticoid-Inducible Kinase SGK1 Invest. Ophthalmol. Vis. Sci., May 1, 2004; 45(5): 1442 - 1449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Pieske, S. R Houser, G. Hasenfuss, and D. M Bers Sodium and the heart: a hidden key factor in cardiac regulation Cardiovasc Res, March 15, 2003; 57(4): 871 - 872. [Full Text] [PDF]
|
|