title: Altered stress stimulation of inward rectifier potassium channels in Andersen-Tawil syndrome.
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.
authors: Department of Biochemistry I-Cation Channel Group, Ruhr University Bochum, Bochum, Germany. guiscard.seebohm@gmx.de
authors: Guiscard
authors: G
authors: Seebohm
authors: Nathalie
authors: N
authors: Strutz-Seebohm
authors: Oana N
authors: ON
authors: Ursu
authors: Regina
authors: R
authors: Preisig-Müller
authors: Marylou
authors: M
authors: Zuzarte
authors: Elaine V
authors: EV
authors: Hill
authors: Marie-Cécile
authors: MC
authors: Kienitz
authors: Said
authors: S
authors: Bendahhou
authors: Michael
authors: M
authors: Fauler
authors: Daniel
authors: D
authors: Tapken
authors: Niels
authors: N
authors: Decher
authors: Anthony
authors: A
authors: Collins
authors: Karin
authors: K
authors: Jurkat-Rott
authors: Klaus
authors: K
authors: Steinmeyer
authors: Frank
authors: F
authors: Lehmann-Horn
authors: Jürgen
authors: J
authors: Daut
authors: Jeremy M
authors: JM
authors: Tavaré
authors: Lutz
authors: L
authors: Pott
authors: Wilhelm
authors: W
authors: Bloch
authors: Florian
authors: F
authors: Lang
mesh_terms: D050030:Andersen Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D005260:Female; D005938:Glucocorticoids / Q000627:therapeutic use; D006168:Guinea Pigs; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014982:Xenopus laevis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D005938:Glucocorticoids; D017874:Immediate-Early Proteins; D050505:Mutant Proteins; D019869:Phosphatidylinositol 3-Kinases; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; D011994:Recombinant Proteins; D000099184:Serum-Glucocorticoid Regulated Kinases; C489457:KCNJ2 protein, human; C099489:KCNJ4 protein, human; C489463:Kir2.2 channel; C492139:PIKFYVE protein, human; C403243:SGK3 protein, human