Differential expression of KvLQT1 isoforms across the human ventricular wall.
Long Q-T mutant (KvLQT1) K(+) channels associate with their regulatory subunit IsK to produce the slow component of the delayed rectifier potassium (I(Ks)) cardiac current. The amplitude of KvLQT1 current depends on the expression of a KvLQT1 splice variant (isoform 2) that exerts strong dominant negative effects on the full-length KvLQT1 protein (isoform 1). We used RNase protection assays to determine the relative expression of KvLQT1 isoforms 1 and 2 and IsK mRNAs in human ventricular layers. Overall expression of KvLQT1 and IsK genes was similar in the three layers. However, there was a significant difference in the ratio between KvLQT1 isoforms 1 and 2. Isoform 2 represented 25.2 +/- 2.3%, 31.7 +/- 1.2%, and 24.9 +/- 1.7% of total KvLQT1 expression in left ventricular endocardial, midmyocardial, and epicardial tissues, respectively. Similar data were obtained from right ventricular samples. COS-7 cells were intranuclearly injected with KvLQT1 isoforms 1 or 2 plus IsK cDNAs, using two different isoform 2-to-isoform 1 ratios. Cells injected with an isoform 2-to-isoform 1 ratio mimicking that in the midmyocardium showed a K(+) current with approximately 75% reduced amplitude compared with those injected with a ratio mimicking that in the epicardium. Our results suggest that differential expression of KvLQT1 isoform 2 in endocardial, midmyocardial, and epicardial tissues is responsible for differential I(Ks) amplitude and contributes to the regional action potential heterogeneity observed across the ventricular wall.
Péréon
Y
Y
Physiopathologie et de Pharmacologie Cellulaires et Moléculaires, Institut National de la Santé et de la Recherche Médicale Unité 533, Faculté de Médecine, F-44093 Nantes Cedex, France. yann.pereon@nantes.inserm.fr
Demolombe
S
S
Baró
I
I
Drouin
E
E
Charpentier
F
F
Escande
D
D
D000200:Action Potentials; D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence / Q000235:genetics; D019556:COS Cells; D004274:DNA, Recombinant; D006321:Heart / Q000502:physiology; D006352:Heart Ventricles; D006801:Humans; D066298:In Vitro Techniques; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism
D004274:DNA, Recombinant; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D020033:Protein Isoforms; D012333:RNA, Messenger; C059983:potassium channel protein I(sk)