Abstract
Mutations in the KvLQT1 gene are the cause of the long QT syndrome 1. KvLQT1 gene product is associated with the regulator protein IsK to produce a component of the delayed rectifier K+ current in cardiac myocytes. We identified an N-terminal truncated isoform of the KvLQT1 gene product, referred to as isoform 2. In RNase protection assays, isoform 2 represented 28.1 +/- 0.6% of the total KvLQT1 expression in the human adult ventricle. COS-7 cells injected intranuclearly with KvLQT1 isoform 1 cDNA exhibited a fast-activating K+ current, whereas those injected with a KvLQT1 isoform 1 plus IsK cDNA showed a slow-activating K+ current. Cells injected with KvLQT1 isoform 2 plasmid showed no detectable K+ current. Those injected with a 1/1 isoform 2/isoform 1 ratio showed no detectable K+ current. Those injected with 1/5 and 2/5 ratios showed a K+ current with markedly reduced amplitude. Coexpression of the IsK regulator consistently reduced the dominant negative effects of isoform 2. Our results indicate that KvLQT1 isoform 2 exerts a pronounced negative dominance on isoform 1 channels and that the cardiac KvLQT1 K+ channel complex is composed of at least three different proteins as follows: isoform 1, isoform 2, and IsK.
Highlights
Mutations in the KvLQT1 gene are the most frequent cause of the congenital long QT syndrome, a familial disorder characterized by prolonged cardiac repolarization, syncope, and a high incidence of sudden death [1]
It was determined that KvLQT1 isoform 2, which is constitutively expressed in adult heart muscle, is a strong dominant negative of KvLQT1 isoform 1
Our results demonstrate that the cardiac Kϩ channel responsible for the long QT syndrome 1 is a complex protein assembly composed of isoform 1, isoform 2, and IsK
Summary
(Received for publication, July 15, 1997, and in revised form, December 29, 1997). Sophie Demolombe, Isabelle Baro , Yann Pereon, Jet Bliek, Raha Mohammad-Panah, Helene Pollard, Shabnam Morid, Marcel Mannens, Arthur Wilde, Jacques Barhanin, Flavien Charpentier, and Denis Escande‡. KvLQT1 gene product is associated with the regulator protein IsK to produce a component of the delayed rectifier K؉ current in cardiac myocytes. Our results indicate that KvLQT1 isoform 2 exerts a pronounced negative dominance on isoform 1 channels and that the cardiac KvLQT1 K؉ channel complex is composed of at least three different proteins as follows: isoform 1, isoform 2, and IsK. Our results demonstrate that the cardiac Kϩ channel responsible for the long QT syndrome 1 is a complex protein assembly composed of isoform 1 (the channel pore), isoform 2 (a dominant negative), and IsK (the channel regulator). These findings could have important physiopathological implications
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