Inhibition of cardiac delayed rectifier K+ currents by an antisense oligodeoxynucleotide against IsK (minK) and over-expression of IsK mutant D77N inneonatal mouse hearts
H. Ohyama et al., Inhibition of cardiac delayed rectifier K+ currents by an antisense oligodeoxynucleotide against IsK (minK) and over-expression of IsK mutant D77N inneonatal mouse hearts, PFLUG ARCH, 442(3), 2001, pp. 329-335
The IsK (minK or KCNE1) protein is known to co-assemble with the KvLQT1 (KC
NQ1) protein to form a channel underlying the slowly activating delayed rec
tifier K+ current (I-Ks). Controversy remains as to whether the IsK protein
assembles with ERG (the ethera-go-go-related gene) products to form or mod
ulate the channel underlying the rapidly activating delayed rectifier K+ cu
rrent (I-Kr). We investigated the effects of antisense oligodeoxynucleotide
s (AS-ODN) against IsK and its mutant D77N [which underlies a form of long
QT syndrome (LQT5) in humans] on the delayed rectifier K+ current (I-K) Of
neonatal mouse ventricular myocytes in primary culture. Patch-clamp experim
ents on these cells showed that I-K consists of I-Ks and I-Kr. I-K was not
recorded from ventricular cells transfected with AS-ODN, while it was recor
ded from cells transfected with the corresponding sense oligodeoxynucleotid
es (S-ODN). I-K was not recorded from cells transfected with the D77N mutan
t, and the action potential duration was much longer than in cells transfec
ted with wild-type IsK. Furthermore, HERG could not induce currents in COS-
I cells co-expressed with the D77N mutant and HERG (the human form of ERG).
These results indicate that the IsK protein associates with both KvLQT1 an
d ERG products to modulate I-Kr and I-Ks in cardiac myocytes.