School of Medicine. Department of Physiology, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
School of Medicine. Department of Biochemistry, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.
Pflugers Arch. 2020 Jan;472(1):75-87. doi: 10.1007/s00424-019-02342-8. Epub 2020 Jan 2.
Kv10.1 (Eag1, or KCNH1) is a human potassium-selective channel associated with tumor development. In this work, we study the interaction of the drug dronedarone with Kv10.1. Dronedarone presents two chemical modifications aimed to lessen side effects produced by its parent molecule, the antiarrhythmic amiodarone. Hence, our observations are discussed within the framework of a previously reported interaction of amiodarone with Kv10.1. Additionally, we show new data regarding the interaction of amiodarone with the channels. We found that, unexpectedly, the effect of dronedarone on Kv10.1 differs both quantitatively and qualitatively to that of amiodarone. Among other observations, we found that dronedarone seems to be an open-pore blocker, in contrast to the reported behavior of amiodarone, which seems to inhibit from both open and closed states. Additionally, herein we provide evidence showing that, in spite of their chemical similarity, these molecules inhibit the K conductance by binding to non-overlapping, independent (non-allosterically related) sites. Also, we show that, while amiodarone inhibits the Cole-Moore shift, dronedarone is unable to inhibit this voltage-dependent characteristic of Kv10.1.
Kv10.1（Eag1，或 KCNH1）是一种与肿瘤发生相关的人类钾选择性通道。在这项工作中，我们研究了药物决奈达隆与 Kv10.1 的相互作用。决奈达隆有两个化学修饰，旨在减轻其母体分子抗心律失常胺碘酮产生的副作用。因此，我们的观察结果是在先前报道的胺碘酮与 Kv10.1 的相互作用框架内进行讨论的。此外，我们还展示了有关胺碘酮与通道相互作用的新数据。我们发现，出乎意料的是，决奈达隆对 Kv10.1 的作用在数量和质量上都与胺碘酮不同。在其他观察结果中，我们发现决奈达隆似乎是一种开放通道阻滞剂，与报道的胺碘酮行为相反，胺碘酮似乎从开放和关闭状态都抑制。此外，本文提供的证据表明，尽管它们具有化学相似性，但这些分子通过结合非重叠的、独立的（非变构相关的）位点来抑制 K 电导。此外，我们还表明，虽然胺碘酮抑制 Cole-Moore 位移，但决奈达隆不能抑制 Kv10.1 的这种电压依赖性特征。
