title: KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders.
abstract: BACKGROUND
  The transient outward current I(to) is of critical importance in regulating myocardial electrical properties during the very early phase of the action potential. The auxiliary beta subunit KCNE2 recently was shown to modulate I(to).
  
  
  OBJECTIVE
  The purpose of this study was to examine the contributions of KCNE2 and its two published variants (M54T, I57T) to I(to).
  
  
  METHODS
  The functional interaction between Kv4.3 (alpha subunit of human I(to)) and wild-type (WT), M54T, and I57T KCNE2, expressed in a heterologous cell line, was studied using patch-clamp techniques.
  
  
  RESULTS
  Compared to expression of Kv4.3 alone, co-expression of WT KCNE2 significantly reduced peak current density, slowed the rate of inactivation, and caused a positive shift of voltage dependence of steady-state inactivation curve. These modifications rendered Kv4.3 channels more similar to native cardiac I(to). Both M54T and I57T variants significantly increased I(to) current density and slowed the inactivation rate compared with WT KCNE2. Moreover, both variants accelerated the recovery from inactivation.
  
  
  CONCLUSIONS
  The study results suggest that KCNE2 plays a critical role in the normal function of the native I(to) channel complex in human heart and that M54T and I57T variants lead to a gain of function of I(to), which may contribute to generating potential arrhythmogeneity and pathogenesis for inherited fatal rhythm disorders.
authors.affiliation: Pharmacology Department, Medical School of Xi'an Jiaotong University. Xi'an, Shaanxi, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Wataru
authors.initials: W
authors.lastname: Shimizu
authors.forename: Wei-Guang
authors.initials: WG
authors.lastname: Ding
authors.forename: Seiko
authors.initials: S
authors.lastname: Ohno
authors.forename: Futoshi
authors.initials: F
authors.lastname: Toyoda
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.forename: Wei-Jin
authors.initials: WJ
authors.lastname: Zang
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Shiro
authors.initials: S
authors.lastname: Kamakura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Koonlawee
authors.initials: K
authors.lastname: Nademanee
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.forename: Pedro
authors.initials: P
authors.lastname: Brugada
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
authors.forename: Matteo
authors.initials: M
authors.lastname: Vatta
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Towbin
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
mesh_terms: D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000401:mortality; D002478:Cells, Cultured; D003001:Cloning, Molecular; D016757:Death, Sudden, Cardiac; D004594:Electrophysiology; D005822:Genetic Vectors; D006329:Heart Conduction System / Q000502:physiology; D006801:Humans; D007700:Kinetics; D051605:Kv Channel-Interacting Proteins / Q000235:genetics* / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D009154:Mutation; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics*; D051672:Shal Potassium Channels / Q000502:physiology; D014162:Transfection
chemical_list: C489619:KCNE2 protein, human; C496752:KCNIP2 protein, human; D051605:Kv Channel-Interacting Proteins; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels