title: Up-regulation of Kir2.1 (KCNJ2) by the serum & glucocorticoid inducible SGK3.
abstract: OBJECTIVE
  The serum & glucocorticoid inducible kinase SGK3, an ubiquitously expressed serine/threonine kinase, regulates a variety of ion channels. It has previously been shown that SGK3 upregulates the outwardly rectifying K(+) channel KV11.1, which is expressed in cardiomyocytes. Cardiomyocytes further express the inward rectifier K(+) channel K(ir)2.1, which contributes to maintenance of resting cell membrane potential. Loss-of-function mutations of KCNJ2 encoding K(ir)2.1 result in Andersen-Tawil syndrome with periodic paralysis, cardiac arrhythmia and dysmorphic features. The present study explored whether SGK3 participates in the regulation of K(ir)2.1.
  
  
  METHODS
  cRNA encoding K(ir)2.1 was injected into Xenopus oocytes with and without additional injection of cRNA encoding wild type SGK3, constitutively active (S419D)SGK3 or inactive (K191N)SGK3. Kir2.1 activity was determined by two-electrode voltage-clamp and K(ir)2.1 protein abundance in the cell membrane by immunostaining and subsequent confocal imaging or by chemiluminescence.
  
  
  RESULTS
  Injection of 10 ng cRNA encoding wild type SGK3 and (S419D)SGK3, but not (K191N)SGK3 significantly enhanced K(ir)2.1-mediated currents. SGK inhibitor EMD638683 (50 µM) abrogated (S419D)SGK3-induced up-regulation of K(ir)2.1. Moreover, wild type SGK3 enhanced the channel protein abundance in the cell membrane. The decay of K(ir)2.1-mediated currents following inhibition of channel insertion into the cell membrane by brefeldin A (5 µM) was similar in oocytes coexpressing K(ir)2.1 and SGK3 as in oocytes expressing K(ir)2.1 alone, suggesting that SGK3 influences channel insertion into rather than channel retrieval from the cell membrane.
  
  
  CONCLUSIONS
  SGK3 is a novel regulator of K(ir)2.1.
authors.affiliation: Department of Physiology, University of Tübingen, Tübingen, Germany.
authors.forename: Carlos
authors.initials: C
authors.lastname: Munoz
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Pakladok
authors.forename: Ahmad
authors.initials: A
authors.lastname: Almilaji
authors.forename: Bernat
authors.initials: B
authors.lastname: Elvira
authors.forename: Niels
authors.initials: N
authors.lastname: Decher
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Shumilina
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D020126:Brefeldin A / Q000494:pharmacology; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009865:Oocytes; D024661:Potassium Channels, Inwardly Rectifying / Q000096:biosynthesis* / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000900:Anti-Bacterial Agents; D020126:Brefeldin A; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; C489457:KCNJ2 protein, human; C403243:SGK3 protein, human; D000099184:Serum-Glucocorticoid Regulated Kinases