Vegetative Physiology, Institute for Physiology and Pathophysiology, Philipps-University Marburg, Marburg, Germany,
Vegetative Physiology, Institute for Physiology and Pathophysiology, Philipps-University Marburg, Marburg, Germany.
Cell Physiol Biochem. 2021 Mar 6;55(S3):87-107. doi: 10.33594/000000339.
Potassium channels of the tandem of two-pore-domain (K) family were among the last potassium channels cloned. However, recent progress in understanding their physiological relevance and molecular pharmacology revealed their therapeutic potential and thus these channels evolved as major drug targets against a large variety of diseases. However, after the initial cloning of the fifteen family members there was a lack of potent and/or selective modulators. By now a large variety of K channel modulators (activators and blockers) have been described, especially for TASK-1, TASK-3, TREK-1, TREK2, TRAAK and TRESK channels. Recently obtained crystal structures of K channels, alanine scanning approaches to map drug binding sites, in silico experiments with molecular dynamics simulations (MDs) combined with electrophysiological studies to reveal the mechanism of channel inhibition/activation, yielded a good understanding of the molecular pharmacology of these channels. Besides summarizing drugs that were identified to modulate K channels, the main focus of this article is on describing the differential binding sites and mechanisms of channel modulation that are utilized by the different K channel blockers and activators.
双孔域（K）家族串联的钾通道是最后克隆的钾通道之一。然而，最近在理解其生理相关性和分子药理学方面的进展揭示了它们的治疗潜力，因此这些通道成为针对多种疾病的主要药物靶点。然而，在最初克隆的十五个家族成员之后，缺乏有效的和/或选择性调节剂。到目前为止，已经描述了大量的 K 通道调节剂（激活剂和阻滞剂），特别是对于 TASK-1、TASK-3、TREK-1、TREK2、TRAAK 和 TRESK 通道。最近获得的 K 通道晶体结构、用于映射药物结合位点的丙氨酸扫描方法、与电生理学研究相结合的分子动力学模拟（MDs），揭示了通道抑制/激活的机制，这使得人们对这些通道的分子药理学有了很好的理解。除了总结已确定可调节 K 通道的药物外，本文的主要重点还在于描述不同 K 通道阻滞剂和激活剂所利用的通道调节的差异结合位点和机制。
