title: A molecular mechanism for adrenergic-induced long QT syndrome.
abstract: OBJECTIVE
  This study sought to explore molecular mechanisms underlying the adrenergic-induced QT prolongation associated with KCNQ1 mutations.
  
  
  BACKGROUND
  The most frequent type of congenital long QT syndrome is LQT1, which is caused by mutations in the gene (KCNQ1) that encodes the alpha subunit of the slow component of delayed rectifier K(+) current (IKs) channel. We identified 11 patients from 4 unrelated families that are heterozygous for KCNQ1-G269S. Most patients remained asymptomatic, and their resting corrected QT intervals ranged from normal to borderline but were prolonged significantly during exercise.
  
  
  METHODS
  Wild-type (WT) KCNQ1 and/or KCNQ1-G269S (G269S) were expressed in mammalian cells with KCNE1. IKs-like currents were measured in control conditions or after isoproterenol or protein kinase A (PKA) stimulation using the patch-clamp technique. Additionally, experiments that incorporated the phosphomimetic KCNQ1 substitution, S27D, in WT or KCNQ1-G269S were also performed.
  
  
  RESULTS
  The coexpression of WT-KCNQ1 with varying amounts of G269S decreased IKs, shifted the current-voltage I-V relation of IKs to more positive potentials, and accelerated the IKs deactivation rates in a concentration-dependent manner. In addition, the coexpression of G269S and WT blunted the activation of IKs in response to isoproterenol or PKA stimulation. Lastly, a phosphomimetic substitution in G269S did not show an increased IKs.
  
  
  CONCLUSIONS
  G269S modestly affected IKs in control conditions, but it almost completely blunted IKs responsiveness in conditions that simulate or mimic PKA phosphorylation of KCNQ1. This insensitivity to PKA stimulation may explain why patients with G269S mutation showed an excessive prolongation of QT intervals on exercise.
authors.affiliation: Department of Pharmacology, Medical School of Xi'an Jiaotong University, Xi'an, China; Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan; Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Nobu
authors.initials: N
authors.lastname: Naiki
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Pharmacology, Medical School of Xi'an Jiaotong University, Xi'an, China.
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Zang
authors.affiliation: Department of Physiology, University of Kentucky, Lexington, Kentucky.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Delisle
authors.affiliation: Department of Physiology, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan. Electronic address: horie@belle.shiga-med.ac.jp.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D000293:Adolescent; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002648:Child; D006224:Cricetinae; D003412:Cricetulus; D005080:Exercise Test / Q000187:drug effects / Q000379:methods; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology; D055815:Young Adult
chemical_list: D000318:Adrenergic beta-Agonists; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying
keywords: KCNQ1 mutation; heterologous expression; long QT syndrome; protein kinase A stimulation