The  Serum-­‐  and  Glucocorticoid-­‐Inducible  Kinase  SGK1  and  SGK3  Regulate  hERG  Channel   Expression  via  Ubiquitin  Ligase  Nedd4-­‐2  and  GTPase  Rab11

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Date
2013-08-14
Authors
Lamothe, Shawn
Keyword
hERG , SGK
Abstract
 The  rapidly  activating  delayed  rectifier  potassium   channel  (IKr)  encoded  by  the  human  ether-­a-­go-­go  related  gene  (hERG)  is  a  crucial   component  of cardiac  repolarization  of  the  action  potential.  The   gating  kinetics  of  the  channel  and  the  number  of  channels  on  the  membrane  determine  the   degree  of  current  flowing  through  hERG  channels.  Membrane  channel  density  is  directly   related  to  a  balance  between  protein  trafficking  and  degradation.  While  hERG  channel   trafficking  has  been  studied  in  the  past  decade,  recently  our  lab  and  others  have  made  new   discoveries  regarding  hERG  degradation.  These  studies  show  that  Neural  Down  Regulated   Gene  4  subtype  2  (Nedd4-­‐2)  is  the  ligase  that  covalently  attaches  ubiquitin  to  the  hERG   channel  and  facilitates  degradation  (Albesa  et  al.,  2011;Guo  et  al.,  2012).  Given  these   findings,  my  goal/objective  was  to  study  the  molecular  mechanisms  that  control  the   destructive  effects  of  Nedd4-­‐2  on  the  hERG  channel.  In  the  present  study,  I  demonstrated   that  overexpression  of  the  stress-­‐responsive  serum-­‐  and  glucocorticoid-­‐inducible  kinase   (SGK)  isoforms  SGK1  and  SGK3  increase  the  current  and  expression  level  of  the  membrane-­‐ localized  mature  proteins  of  hERG  channels  stably  expressed  in  HEK  293  (hERG-­‐HEK)  cells.   I  have  found  that  the  overexpression  of  SGK1  and  SGK3  increased  Nedd4-­‐2   phosphorylation,  which  is  known  to  inhibit  Nedd4-­‐2  activity.  Furthermore,  the  synthetic   glucocorticoid,  dexamethasone,  increased  the  current  and  abundance  of  mature  ERG   proteins  in  both  hERG-­‐HEK  cells  and  neonatal  rat  cardiac  myocytes  through  the   enhancement  of  SGK1  but  not  SGK3  expression.  Additionally,  disruption  of  Rab11  proteins led  to  a  complete  elimination  of  SGK-­‐mediated  increase  in  hERG  expression.  These  results   indicate  that  SGK  enhances  the  expression  level  of  mature  hERG  channels  by  inhibiting   Nedd4-­‐2  as  well  as  by  promoting  Rab11-­‐mediated  hERG  recycling.
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