Referenced in: none

Automatically associated channels: Kir2.1

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

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

Journal, date & volume: FASEB J., 2012 Feb , 26, 513-22

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/22002906

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.