Doctoral School of Biology, Faculty of Biology, "Alexandru Ioan Cuza" University of Iasi, Iasi, Romania.
Chem Biol Drug Des. 2019 Sep;94(3):1596-1614. doi: 10.1111/cbdd.13571. Epub 2019 Jun 19.
The K ion channels comprising the two-pore domain (K2P) family have specific biophysical roles in generating the critical regulatory K current. Ion flow through K2P channels and, implicitly, channel regulation is mediated by diverse metabolic and physical inputs such as mechanical stimulation, interaction with lipids or endogenous regulators, intra- or extracellular pH, and phosphorylation, while their function can be finely tuned by chemical compounds. In the latter category, some drug-channel interactions can lead to side effects or have clinical action, while identifying novel chemical modulators of K2Ps is an area of intense research. Due to their cellular and therapeutic importance, much attention was turned to these channels in recent years and several experimental approaches have pinpointed the molecular determinants of K2P chemical modulation. Given their unique structural features and properties, chemical modulators act on K2P channels in multiple and diverse ways. In this review, the particularities of K2P modulation by chemical compounds, such as binding modality, affinity, or position, are identified, synthesized, and linked to structural and functional properties in order to refer to how activators and blockers modify channel function and vice versa, focusing on specificity related to protein structure (and its modification) and cross-linking information among different subfamilies.
由双孔域 (K2P) 家族组成的 K 离子通道在产生关键调节性 K 电流方面具有特定的生物物理作用。离子通过 K2P 通道的流动，以及通道调节，隐含地受到多种代谢和物理输入的影响，如机械刺激、与脂质或内源性调节剂的相互作用、细胞内外 pH 值和磷酸化，而其功能可以通过化学化合物进行精细调节。在后一类中，一些药物-通道相互作用可能导致副作用或具有临床作用，而鉴定 K2P 的新型化学调节剂是一个研究热点。由于它们的细胞和治疗重要性，近年来人们对这些通道给予了极大的关注，并且几种实验方法已经确定了 K2P 化学调节的分子决定因素。鉴于它们独特的结构特征和性质，化学调节剂以多种不同的方式作用于 K2P 通道。在这篇综述中，确定了化学化合物对 K2P 的调制的特殊性，如结合模式、亲和力或位置，并将其与结构和功能特性联系起来，以便参考激活剂和抑制剂如何改变通道功能，反之亦然，重点关注与蛋白质结构（及其修饰）和不同亚家族之间的交联信息相关的特异性。
