Pfizer NPRU, Cambridge, UK.
Icagen, Durham, NC, USA.
Br J Pharmacol. 2018 Jun;175(12):2272-2283. doi: 10.1111/bph.14098. Epub 2017 Dec 29.
TREK two-pore-domain potassium (K ) channels play a critical role in regulating the excitability of somatosensory nociceptive neurons and are important mediators of pain perception. An understanding of the roles of TREK channels in pain perception and, indeed, in other pathophysiological conditions, has been severely hampered by the lack of potent and/or selective activators and inhibitors. In this study, we describe a new, selective opener of TREK channels, GI-530159.
The effect of GI-530159 on TREK channels was demonstrated using Rb efflux assays, whole-cell and single-channel patch-clamp recordings from recombinant TREK channels. The expression of K 2.1 (TREK1), K 10.1 (TREK2) and K 4.1 (TRAAK) channels was determined using transcriptome analysis from single dorsal root ganglion (DRG) cells. Current-clamp recordings from cultured rat DRG neurons were used to measure the effect of GI-530159 on neuronal excitability.
For recombinant human TREK1 channels, GI-530159 had similar low EC values in Rb efflux experiments and electrophysiological recordings. It activated TREK2 channels, but it had no detectable action on TRAAK channels nor any significant effect on other K channels tested. Current-clamp recordings from cultured rat DRG neurones showed that application of GI-530159 at 1 μM resulted in a significant reduction in firing frequency and a small hyperpolarization of resting membrane potential.
This study provides pharmacological evidence for the presence of mechanosensitive TREK K channels in sensory neurones and suggests that development of selective K channel openers like GI-530159 could aid in the development of novel analgesic agents.
This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
TREK 双孔钾（K）通道在调节躯体感觉伤害性神经元的兴奋性方面起着关键作用，是疼痛感知的重要介质。对 TREK 通道在疼痛感知中的作用的理解，实际上是在其他病理生理条件下的理解，由于缺乏有效和/或选择性的激动剂和抑制剂而受到严重阻碍。在这项研究中，我们描述了一种新的、选择性的 TREK 通道开放剂，GI-530159。
使用 Rb 外排测定、重组 TREK 通道的全细胞和单通道膜片钳记录，证明 GI-530159 对 TREK 通道的作用。使用单个背根神经节（DRG）细胞的转录组分析来确定 K 2.1（TREK1）、K 10.1（TREK2）和 K 4.1（TRAAK）通道的表达。使用培养的大鼠 DRG 神经元的电流钳记录来测量 GI-530159 对神经元兴奋性的影响。
对于重组人 TREK1 通道，GI-530159 在 Rb 外排实验和电生理记录中的 EC 值相似。它激活 TREK2 通道，但对 TRAAK 通道没有检测到作用，对测试的其他 K 通道也没有显著影响。培养的大鼠 DRG 神经元的电流钳记录显示，应用 1μM 的 GI-530159 导致放电频率显著降低和静息膜电位的轻微超极化。
这项研究为感觉神经元中存在机械敏感的 TREK K 通道提供了药理学证据，并表明开发像 GI-530159 这样的选择性 K 通道开放剂可能有助于开发新型的镇痛剂。
本文是一个关于靶向离子通道治疗慢性疼痛的最新进展的专题部分的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
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