title: A dominant negative isoform of the long QT syndrome 1 gene product.
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.
authors.affiliation: Laboratoire de Physiopathologie et de Pharmacologie Cellulaires et Mol-eculaires, INSERM CJF96-01, H-opital H-otel-Dieu, Nantes, France.
authors.forename: S
authors.initials: S
authors.lastname: Demolombe
authors.forename: I
authors.initials: I
authors.lastname: Baró
authors.forename: Y
authors.initials: Y
authors.lastname: Péréon
authors.forename: J
authors.initials: J
authors.lastname: Bliek
authors.forename: R
authors.initials: R
authors.lastname: Mohammad-Panah
authors.forename: H
authors.initials: H
authors.lastname: Pollard
authors.forename: S
authors.initials: S
authors.lastname: Morid
authors.forename: M
authors.initials: M
authors.lastname: Mannens
authors.forename: A
authors.initials: A
authors.lastname: Wilde
authors.forename: J
authors.initials: J
authors.lastname: Barhanin
authors.forename: F
authors.initials: F
authors.lastname: Charpentier
authors.forename: D
authors.initials: D
authors.lastname: Escande
mesh_terms: D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D003001:Cloning, Molecular; D018076:DNA, Complementary; D005799:Genes, Dominant; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D012689:Sequence Homology, Nucleic Acid
chemical_list: D018076:DNA, Complementary; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated