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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
Long Q-T mutant (KvLQT1) K+ channels associate with their regulatory subunit IsK to produce the slow component of the delayed rectifier potassium (IKs) 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 ~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 IKs amplitude and contributes to the regional action potential heterogeneity observed across the ventricular wall.
delayed rectifier potassium current; IsK; messenger ribonucleic acid levels; long Q-T syndrome
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