KCNE2 modulation of Kv4.3 current and its potential role in fatal rhythm disorders.
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.
Wu
Jie
J
Pharmacology Department, Medical School of Xi'an Jiaotong University. Xi'an, Shaanxi, China.
Shimizu
Wataru
W
Ding
Wei-Guang
WG
Ohno
Seiko
S
Toyoda
Futoshi
F
Itoh
Hideki
H
Zang
Wei-Jin
WJ
Miyamoto
Yoshihiro
Y
Kamakura
Shiro
S
Matsuura
Hiroshi
H
Nademanee
Koonlawee
K
Brugada
Josep
J
Brugada
Pedro
P
Brugada
Ramon
R
Vatta
Matteo
M
Towbin
Jeffrey A
JA
Antzelevitch
Charles
C
Horie
Minoru
M
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
C489619:KCNE2 protein, human; C496752:KCNIP2 protein, human; D051605:Kv Channel-Interacting Proteins; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels