Drug induced Long QT syndrome results primarily from block of the cardiac potassium channel heRG (human-ether-a-gogo related gene). In some cases prolongation of the QT interval can result in the lethal arrhythmia torsade de pointes, an arrhythmia characterized by a rapid heart rate and severely compromised cardiac output. Many patients requiring medication present with abnormal serum electrolyte levels due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, alcoholism and aging. Extracellular cations have significant influence on HERG channel gating and in some instances they have been shown to alter drug block of heRG. however, the mechanisms by which drug block is altered in different extracellular cation solutions are not well understood. In this study, heRG block by quinidine and cisapride was assessed in extracellular solutions of calcium, potassium, rubidium, cesium and tetraethylammonium (TeA) using two-electrode voltage clamping of Xenopus oocytes. Consistent with previous reports we show that increases in extracellular potassium reduce heRG block by quinidine and cisapride. We also show that increasing extracellular rubidium and cesium reduced heRG block by quinidine and cisapride whereas increasing extracellular calcium and extracellular TeA did not alter heRG block by quinidine and cisapride. These results demonstrate that at lower extracellular potassium concentrations, the permeant ion is almost exclusively responsible for the reduction in quinidine and cisapride block of heRG due to increases in extracellular potassium.
Recently we reported that the KCNE2 gene is an estrogen-responsive gene and its transcripts are upregulated 6 fold by estrogen (E2) in ovariectomized (ovx) mice 1 . We have also shown that cardiac Kv4.3 transcripts were downregulated ~2 fold by E2 2 . As the effect of E2 treatment was more powerful on KCNE2 upregulation than Kv4.3 downregulation, we hypothesized that cardiac Kv4.3 and KCNE2 have different sensitivities to heart E2 concentrations [E2]. We measured heart [E2] together with KCNE2 and Kv4.3 transcript levels in 4 estrogenic conditions: i) E2-depleted (anastrozole treated mice, [E2]¼4.250.4 pg/ml n¼4; ii) low E2 (ovx sham, [E2]¼1651.4 pg/ml n¼3 and diestrus [E2]¼20.251.5 n¼4), iii) intermediate E2 (male [E2]¼3553 pg/ml, n¼6) and iv) high E2 (ovx mice treated with E2, [E2]¼62.752.9 pg/ml, n¼3). Kv4.3 transcript levels were not affected by heart [E2] lower than 35 pg/ml whereas KCNE2 transcript levels were very sensitive to this range of heart [E2], reaching a ~10 fold increase from low to intermediate heart [E2], saturating at 35 pg/ml. The fact that Kv4.3 levels were unaffected by anastrozole treatment, whereas KCNE2 levels were dramatically reduced by ~8 fold by anastrozole, further supports the finding that KCNE2 upregulation can take place at very low E2 levels. The downregulation of Kv4.3 transcripts were only evident at high estrogenic conditions, whereas KCNE2 remains at its maximum. As Kv4.3 is one of the molecular correlate of I to,f and it has also been shown that KCNE2 can potentiate Kv4.3 currents in the expression system, we speculate that the relative expression of KCNE2 and Kv4.3 as defined by heart [E2] will determine I to,f amplitude.
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