Yu Rilei, Liu Huijie, Wang Baishi, Harvey Peta J, Wei Ningning, Chu Yanyan
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China Qingdao 266003 China
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology Qingdao 266003 China.
RSC Adv. 2020 Jan 10;10(4):2141-2145. doi: 10.1039/c9ra08829f. eCollection 2020 Jan 8.
TRPV1 is a ligand-gated ion channel and plays an important role in detecting noxious heat and pain with an unknown mechanism. RhTx from Chinese red-headed centipede activates the TRPV1 channel through the heat activation pathway by binding to the outer pore region, and causes extreme pain. Here, we synthesized RhTx and its retro-isomer RL-RhTx. Their structures were investigated by their circular dichroic spectra and NMR spectra. The effect of RhTx and RL-RhTx on the currents of wild-type and mutants of TRPV1 indicated that RL-RhTx have comparable TRPV1 activation responses to RhTx. A mutagenesis study showed that four TRPV1 residues, including Leu461, Asp602, Tyr632 and Thr634, significantly contributed to the activation effects of RL-RhTx and RhTx, and both peptides probably bind with TRPV1 in similar binding modes. As a novel TRPV1 activator, RL-RhTx provides an essential powerful tool for the investigation of activation mechanisms of TRPV1.
瞬时受体电位香草酸亚型1（TRPV1）是一种配体门控离子通道，在检测有害热和疼痛方面发挥着重要作用，但其机制尚不清楚。来自中国红头蜈蚣的RhTx通过与外孔区域结合，经热激活途径激活TRPV1通道，并引起剧痛。在此，我们合成了RhTx及其反向异构体RL-RhTx。通过圆二色光谱和核磁共振光谱对它们的结构进行了研究。RhTx和RL-RhTx对TRPV1野生型和突变体电流的影响表明，RL-RhTx对TRPV1的激活反应与RhTx相当。诱变研究表明，包括Leu461、Asp602、Tyr632和Thr634在内的四个TRPV1残基对RL-RhTx和RhTx的激活作用有显著贡献，且两种肽可能以相似的结合模式与TRPV1结合。作为一种新型的TRPV1激活剂，RL-RhTx为研究TRPV1的激活机制提供了一种重要的有力工具。
