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

Guiscard Seebohm, Nathalie Strutz-Seebohm, Oana N Ursu, Regina Preisig-Müller, Marylou Zuzarte, Elaine V Hill, Marie-Cécile Kienitz, Said Bendahhou, Michael Fauler, Daniel Tapken, Niels Decher, Anthony Collins, Karin Jurkat-Rott, Klaus Steinmeyer, Frank Lehmann-Horn, Jürgen Daut, Jeremy M Tavaré, Lutz Pott, Wilhelm Bloch, Florian Lang

Research output: Contribution to journalArticle (Academic Journal)peer-review

14 Citations (Scopus)

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.
Translated title of the contributionAltered stress stimulation of inward rectifier potassium channels in Andersen-Tawil syndrome
Original languageEnglish
Pages (from-to)513 - 522
Number of pages10
JournalFASEB Journal
Volume26
Issue number2
DOIs
Publication statusPublished - Feb 2012

Bibliographical note

Other: First published on-line 14th October 2011

Keywords

  • Mutant Proteins
  • Animals
  • Recombinant Proteins
  • Guinea Pigs
  • HeLa Cells
  • HEK293 Cells
  • Humans
  • Protein-Serine-Threonine Kinases
  • Glucocorticoids
  • Phosphatidylinositol 3-Kinases
  • Xenopus laevis
  • Andersen Syndrome
  • Potassium Channels, Inwardly Rectifying
  • Immediate-Early Proteins
  • Oocytes
  • Protein Structure, Tertiary
  • Myocytes, Cardiac
  • Signal Transduction
  • Female
  • Stress, Physiological

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