Department of Cardiovascular and Metabolic Medicine and Liverpool Centre for Cardiovascular Science, University of Liverpool, Liverpool, UK.
Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
Br J Pharmacol. 2024 Sep;181(18):3380-3400. doi: 10.1111/bph.16390. Epub 2024 May 19.
The canonical K6.2/SUR2A ventricular K channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of K channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second K channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active K6.1-containing K channel in ventricular cardiomyocytes.
Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation.
Our data show a ventricular K conductance whose biophysical characteristics and response to pharmacological modulation were consistent with K6.1-containing channels. These K6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active.
We conclude there are two functionally distinct populations of ventricular K channels: constitutively active K6.1-containing channels that play an important role in fine-tuning the action potential and K6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether K6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.
经典的 K6.2/SUR2A 心室 K 通道对 ATP 高度敏感，在正常生理条件下保持关闭。只有当长时间的代谢衰竭导致显著的 ATP 耗竭，然后缩短动作电位以减少收缩活动时，这些通道才会激活。K 通道的药理学激活具有心脏保护作用，但从生理上讲，如果这些通道仅在极端代谢应激下开放，就很难理解它们如何保护心脏。第二种 K 通道的存在可以帮助解释这一点。在这里，我们描述了在心室肌细胞中组成型激活的 K6.1 含 K 通道的生物物理和药理学特性。
使用大鼠心室肌细胞的膜片钳记录，结合明确的药理学调节剂，用于描述这些新鉴定的 K 通道。动作电位记录、钙（Fluo-4）荧光测量和收缩功能的视频边缘检测用于评估通道调制的功能后果。
我们的数据显示了一种心室 K 电导，其生物物理特性和对药理学调节剂的反应与含有 K6.1 的通道一致。这些 K6.1 含有的通道缺乏经典通道的 ATP 敏感性，并且是组成型激活的。
我们得出结论，存在两种功能上不同的心室 K 通道群体：组成型激活的 K6.1 含有的通道，在精细调节动作电位方面发挥重要作用；以及 K6.2/SUR2A 通道，在长时间缺血时激活，对灾难性的 ATP 耗竭提供晚期保护。需要进一步研究以确定 K6.1 是否是综合体外致心律失常性评估（CiPA）心脏安全性筛选中被忽视的靶点。
