The Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine , Indianapolis, Indiana.
Wonkwang University School of Medicine and Hospital, Iksan, South Korea.
Am J Physiol Heart Circ Physiol. 2018 Aug 1;315(2):H375-H388. doi: 10.1152/ajpheart.00479.2017. Epub 2018 Apr 20.
Apamin-sensitive small-conductance Ca-activated K (SK) current ( I) is encoded by Ca-activated K channel subfamily N ( KCNN) genes. I importantly contributes to cardiac repolarization in conditions associated with reduced repolarization reserve. To test the hypothesis that I inhibition contributes to drug-induced long QT syndrome (diLQTS), we screened for KCNN variants among patients with diLQTS, determined the properties of heterologously expressed wild-type (WT) and variant KCNN channels, and determined if the 5-HT receptor antagonist ondansetron blocks I. We searched 2,306,335 records in the Indiana Network for Patient Care and found 11 patients with diLQTS who had DNA available in the Indiana Biobank. DNA sequencing discovered a heterozygous KCNN2 variant (p.F503L) in a 52-yr-old woman presenting with corrected QT interval prolongation at baseline (473 ms) and further corrected QT interval lengthening (601 ms) after oral administration of ondansetron. That patient was also heterozygous for the p.S38G and p.P2835S variants of the QT-controlling genes KCNE1 and ankyrin 2, respectively. Patch-clamp experiments revealed that the p.F503L KCNN2 variant heterologously expressed in human embryonic kidney (HEK)-293 cells augmented Ca sensitivity, increasing I density. The fraction of total F503L-KCNN2 protein retained in the membrane was higher than that of WT KCNN2 protein. Ondansetron at nanomolar concentrations inhibited WT and p.F503L SK2 channels expressed in HEK-293 cells as well as native SK channels in ventricular cardiomyocytes. Ondansetron-induced I inhibition was also demonstrated in Langendorff-perfused murine hearts. In conclusion, the heterozygous p.F503L KCNN2 variant increases Ca sensitivity and I density in transfected HEK-293 cells. Ondansetron at therapeutic (i.e., nanomolar) concentrations is a potent I blocker. NEW & NOTEWORTHY We showed that ondansetron, a 5-HT receptor antagonist, blocks small-conductance Ca-activated K (SK) current. Ondansetron may be useful in controlling arrhythmias in which increased SK current is a likely contributor. However, its SK-blocking effects may also facilitate the development of drug-induced long QT syndrome.
阿帕米敏感的小电导钙激活钾（SK）电流（I）由钙激活钾通道亚家族 N（KCNN）基因编码。I 对与复极化储备减少相关的心脏复极有重要贡献。为了检验 I 抑制有助于药物引起的长 QT 综合征（diLQTS）的假说，我们在 diLQTS 患者中筛选 KCNN 变体，确定异源表达的野生型（WT）和变体 KCNN 通道的特性，并确定 5-HT 受体拮抗剂昂丹司琼是否阻断 I。我们在印第安纳州患者护理网络中搜索了 2306335 条记录，并在印第安纳生物库中找到了 11 名具有 diLQTS 且 DNA 可用的患者。DNA 测序在一名 52 岁女性中发现了一种杂合的 KCNN2 变体（p.F503L），该女性在基线时（473ms）出现校正 QT 间期延长，口服昂丹司琼后进一步延长 QT 间期（601ms）。该患者还分别携带控制基因 KCNE1 和锚蛋白 2 的 p.S38G 和 p.P2835S 变体的杂合子。膜片钳实验显示，在人胚肾（HEK）-293 细胞中异源表达的 p.F503L KCNN2 变体增加了 Ca 敏感性，增加了 I 密度。保留在膜中的总 F503L-KCNN2 蛋白的分数高于 WT KCNN2 蛋白。在纳摩尔浓度下，昂丹司琼抑制了在 HEK-293 细胞中表达的 WT 和 p.F503L SK2 通道以及心室心肌细胞中的天然 SK 通道。在 Langendorff 灌流的鼠心中也证明了昂丹司琼诱导的 I 抑制。总之，杂合的 p.F503L KCNN2 变体增加了转染的 HEK-293 细胞中 Ca 敏感性和 I 密度。治疗（即纳摩尔）浓度的昂丹司琼是一种有效的 I 阻断剂。新与值得注意的是，我们发现 5-HT 受体拮抗剂昂丹司琼可阻断小电导钙激活钾（SK）电流。在 SK 电流可能是主要贡献者的心律失常中，昂丹司琼可能有用。然而，其 SK 阻断作用也可能促进药物引起的长 QT 综合征的发展。
