Inhibition of cardiac delayed rectifier K+ currents by an antisense oligodeoxynucleotide against IsK (minK) and over-expression of IsK mutant D77N inneonatal mouse hearts

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.