LE135，一种视黄酸受体拮抗剂，通过直接激活 TRP 通道产生疼痛。
LE135, a retinoid acid receptor antagonist, produces pain through direct activation of TRP channels.
机构信息
College of Pharmacy, South-Central University for Nationalities, Wuhan, China; Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
出版信息
Br J Pharmacol. 2014 Mar;171(6):1510-20. doi: 10.1111/bph.12543.
BACKGROUND AND PURPOSE
Retinoids, through their activation of retinoic acid receptors (RARs) and retinoid X receptors, regulate diverse cellular processes, and pharmacological intervention in their actions has been successful in the treatment of skin disorders and cancers. Despite the many beneficial effects, administration of retinoids causes irritating side effects with unknown mechanisms. Here, we demonstrate that LE135 [4-(7,8,9,10-tetrahydro-5,7,7,10,10-pentamethyl-5H-benzo[e]naphtho[2,3-b][1,4]diazepin-13-yl)benzoic acid], a selective antagonist of RARβ , is a potent activator of the capsaicin (TRPV1) and wasabi (TRPA1) receptors, two critical pain-initiating cation channels.
EXPERIMENTAL APPROACH
We performed to investigate the excitatory effects of LE135 on TRPV1 and TRPA1 channels expressed in HEK293T cells and in dorsal root ganglia neurons with calcium imaging and patch-clamp recordings. We also used site-directed mutagenesis of the channels to determine the structural basis of LE135-induced activation of TRPV1 and TRPA1 channels and behavioural testing to examine if pharmacological inhibition and genetic deletion of the channels affected LE135-evoked pain-related behaviours.
KEY RESULTS
LE135 activated both the capsaicin receptor (TRPV1) and the allyl isothiocyanate receptor (TRPA1) heterologously expressed in HEK293T cells and endogenously expressed by sensory nociceptors. Mutations disrupting the capsaicin-binding site attenuated LE135 activation of TRPV1 channels and a single mutation (K170R) eliminated TRPA1 activity evoked by LE135. Intraplantar injection of LE135 evoked pain-related behaviours. Both TRPV1 and TRPA1 channels were involved in LE135-elicited pain-related responses, as shown by pharmacological and genetic ablation studies.
CONCLUSIONS AND IMPLICATIONS
This blocker of retinoid acid signalling also exerted non-genomic effects through activating the pain-initiating TRPV1 and TRPA1 channels.
背景与目的
维甲酸通过激活视黄酸受体（RARs）和视黄醛 X 受体（RXRs），调节多种细胞过程，其作用的药理学干预已成功用于治疗皮肤疾病和癌症。尽管有许多有益的效果，但维甲酸的给药会引起刺激性的副作用，其机制尚不清楚。在这里，我们证明 LE135[4-(7,8,9,10-四氢-5,7,7,10,10-五甲基-5H-苯并[e]萘并[2,3-b][1,4]二氮杂环庚-13-基)苯甲酸]，一种 RARβ选择性拮抗剂，是辣椒素（TRPV1）和山葵（TRPA1）受体的有效激活剂，这两种受体是两个关键的起始疼痛阳离子通道。
实验方法
我们进行了研究，以用钙成像和膜片钳记录来研究 LE135 对表达于 HEK293T 细胞和背根神经节神经元中的 TRPV1 和 TRPA1 通道的兴奋作用。我们还使用通道的定点突变来确定 LE135 诱导的 TRPV1 和 TRPA1 通道激活的结构基础，并进行行为测试以检查通道的药理学抑制和基因缺失是否影响 LE135 诱发的与疼痛相关的行为。
主要结果
LE135 激活了在 HEK293T 细胞中异源表达的辣椒素受体（TRPV1）和丙烯基异硫氰酸酯受体（TRPA1）以及内源性表达于感觉伤害感受器的 TRPV1 和 TRPA1 通道。破坏辣椒素结合位点的突变减弱了 LE135 对 TRPV1 通道的激活，而单个突变（K170R）消除了 LE135 诱发的 TRPA1 活性。足底内注射 LE135 引起与疼痛相关的行为。如药理学和基因消融研究所示，TRPV1 和 TRPA1 通道均参与了 LE135 诱发的与疼痛相关的反应。
结论和意义
这种视黄酸信号传导的阻断剂还通过激活起始疼痛的 TRPV1 和 TRPA1 通道产生非基因组效应。
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