Altered stress stimulation of inward rectifier potassium channels in Andersen-Tawil syndrome

FASEB J. 2012 Feb;26(2):513-22. doi: 10.1096/fj.11-189126. Epub 2011 Oct 14.

Abstract

Inward rectifier potassium channels of the Kir2 subfamily are important determinants of the electrical activity of brain and muscle cells. Genetic mutations in Kir2.1 associate with Andersen-Tawil syndrome (ATS), a familial disorder leading to stress-triggered periodic paralysis and ventricular arrhythmia. To identify the molecular mechanisms of this stress trigger, we analyze Kir channel function and localization electrophysiologically and by time-resolved confocal microscopy. Furthermore, we employ a mathematical model of muscular membrane potential. We identify a novel corticoid signaling pathway that, when activated by glucocorticoids, leads to enrichment of Kir2 channels in the plasma membranes of mammalian cell lines and isolated cardiac and skeletal muscle cells. We further demonstrate that activation of this pathway can either partly restore (40% of cases) or further impair (20% of cases) the function of mutant ATS channels, depending on the particular Kir2.1 mutation. This means that glucocorticoid treatment might either alleviate or deteriorate symptoms of ATS depending on the patient's individual Kir2.1 genotype. Thus, our findings provide a possible explanation for the contradictory effects of glucocorticoid treatment on symptoms in patients with ATS and may open new pathways for the design of personalized medicines in ATS therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Andersen Syndrome / drug therapy
  • Andersen Syndrome / genetics
  • Andersen Syndrome / metabolism*
  • Animals
  • Female
  • Glucocorticoids / therapeutic use
  • Guinea Pigs
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Immediate-Early Proteins / metabolism
  • In Vitro Techniques
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Myocytes, Cardiac / metabolism
  • Oocytes / metabolism
  • Phosphatidylinositol 3-Kinases / metabolism
  • Potassium Channels, Inwardly Rectifying / chemistry
  • Potassium Channels, Inwardly Rectifying / genetics
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Stress, Physiological
  • Xenopus laevis

Substances

  • Glucocorticoids
  • Immediate-Early Proteins
  • KCNJ2 protein, human
  • KCNJ4 protein, human
  • Kir2.2 channel
  • Mutant Proteins
  • Potassium Channels, Inwardly Rectifying
  • Recombinant Proteins
  • Phosphatidylinositol 3-Kinases
  • PIKFYVE protein, human
  • Protein-Serine-Threonine Kinases
  • SGK3 protein, human
  • serum-glucocorticoid regulated kinase