Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences , Southern Medical University , Guangzhou 510515 , China.
Department of Biology, Faculty of Science , Hong Kong Baptist University , Kowloon Tong , Hong Kong Special Administrative Region , China.
ACS Chem Neurosci. 2019 Jun 19;10(6):2786-2793. doi: 10.1021/acschemneuro.9b00010. Epub 2019 Apr 17.
K2P potassium channels stabilize the resting membrane potential in nearly all cells and have been implicated in several neuronal, cardiovascular, and immune diseases. DCPIB, a known specific and potent inhibitor of volume-regulated anion channels (VRAC), has been reported to activate TREK1 and TREK2 in astrocytes and in vitro recently. In the present study, we demonstrated DCPIB also voltage dependently activated TRAAK besides TREK1/TREK2, showing DCPIB activated all TREK subfamily members. In contrast, the compound potently inhibited several other K2P channels with no voltage dependence, including TRESK, TASK1, and TASK3. DCPIB displayed superior selectivity toward TRESK with an IC of 0.14 μM, demonstrating at least 100-fold higher affinity over TREK1/TRAAK channels. Furthermore, the impaired ion selectivity filter region greatly impaired the activating effect of DCPIB on TREK1 but not the inhibitory effect of DCPIB on TRESK. This indicates distinct molecular determinants underlying the effect of DCPIB on TREK1 or TRESK channels. Our results showed that DCPIB played diverse effects on K2P channels and could be a useful tool for further investigating structure-function studies of K2P channels.
K2P 钾通道在几乎所有细胞中稳定静息膜电位，并与几种神经元、心血管和免疫疾病有关。最近有报道称，已知的容积调节阴离子通道 (VRAC) 的特异性和强效抑制剂 DCPIB，可在星形胶质细胞中和体外激活 TREK1 和 TREK2。在本研究中，我们证明了 DCPIB 还可电压依赖性地激活除 TREK1/TREK2 之外的 TRAAK，表明 DCPIB 激活了所有 TREK 亚家族成员。相比之下，该化合物还强力抑制了几种其他无电压依赖性的 K2P 通道，包括 TRESK、TASK1 和 TASK3。DCPIB 对 TRESK 表现出优异的选择性，IC50 为 0.14 μM，表明对 TREK1/TRAAK 通道的亲和力至少高 100 倍。此外，离子选择性滤过区的损伤大大削弱了 DCPIB 对 TREK1 的激活作用，但对 DCPIB 对 TRESK 的抑制作用没有影响。这表明 DCPIB 对 TREK1 或 TRESK 通道的作用存在不同的分子决定因素。我们的结果表明，DCPIB 对 K2P 通道具有多种作用，可能是进一步研究 K2P 通道结构-功能研究的有用工具。
