Serum and glucocorticoid inducible kinases in the regulation of the cardiac sodium channel SCN5A.
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 (S422D)SGK1, 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.
Boehmer
Christoph
C
Department of Physiology I, University of Tübingen, Gmelinstrasse 5, D-72076, Tübingen, Germany.
Wilhelm
Viktoria
V
Palmada
Monica
M
Wallisch
Sabine
S
Henke
Guido
G
Brinkmeier
Heinrich
H
Cohen
Philip
P
Pieske
Burkert
B
Lang
Florian
F
D000818:Animals; D005938:Glucocorticoids / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D018075:RNA, Complementary / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D018075:RNA, Complementary; D015222:Sodium Channels; D000099184:Serum-Glucocorticoid Regulated Kinases; C568320:SCN5A protein, human