The investigation of allosteric regulation mechanism of analgesic effect using SD rat taste bud tissue biosensor
The investigation of allosteric regulation mechanism of analgesic effect using SD rat taste bud tissue biosensor
复制标题
利用SD大鼠味蕾组织生物传感器研究镇痛作用的变构调节机制
DOI：
10.1016/j.bios.2018.11.046
复制
发表时间：
2019
影响因子：
12.6
通讯作者：
Pang Guangchang
中科院分区：
文献类型：
--
作者：
Xiao Sa;Zhang Yanqing;Song Panpan;Xie Junbo;Pang Guangchang
本研究采用淀粉-海藻酸钠交联固定法制备了味蕾组织生物传感器。以辣椒素为TRPV 1有害离子通道激活剂，研究了6种不同物质对辣椒素的拮抗动力学。结果表明，辣椒平、AMG 517、龙血素B和延胡索乙素均为辣椒素的竞争性别构调节配体，乌头碱和大麻素则为混合性别构调节配体，兼有非竞争性和竞争性作用。通过分析辣椒素及其竞争性别构调节配体的动力学参数，并比较辛辣物质与内源性大麻素的结构，阐明酰胺基及类似基团在大麻素受体的别构调节和镇痛机制中的重要性。这表明，香草素激活剂打开TRPV 1离子通道，仅传递疼痛和其他伤害性信号，而辣椒素及其竞争性配体能够通过结合内源性大麻素受体激活细胞内G蛋白/PI 3 K/PIP 2信号通路，然后增加细胞内PIP 2水平（增加的PIP 2可以竞争性地取代辣椒素和其他香草素激活剂），从而关闭TRPV 1通道并发挥镇痛作用。阐明这一疼痛和镇痛机制将为研究伤害性信息和筛选潜在的镇痛药物奠定理论基础和新思路。
In this study, a taste bud tissue biosensor was prepared by a starch-sodium alginate cross-linking fixation method. Capsaicin was used as a TRPV1 noxious ion channel activator to investigate the antagonism kinetics of six different substances on capsaicin. The results showed that capsazepine, AMG517, loureirin B, and tetrahydropalmatine were all competitive allosteric regulatory ligands for capsaicin, while aconitine and anandamide were mixed allosteric regulatory ligand that combines non-competition and competition effect. Through analyzing the kinetic parameters of capsaicin and its competitive allosteric regulatory ligands, and comparing the structures between spicy substances and endocannabinoids, the importance of amide groups and similar groups in the allosteric regulation of cannabinoids (CB) receptors and analgesic mechanism was elucidated. This indicates that vanilloid activators turn on the TRPV1 ion channel to transmit only pain and other nociceptive signals, while capsaicin and its competitive ligands are capable of activating intracellular G protein/PI3K/PIP2 signaling pathways by binding to endogenous cannabinoid receptors, and then increase intracellular PIP2 levels (the increasing PIP2 can competitively replace capsaicin and other vanilloid activators), thereby closing the TRPV1 channel and exerting the analgesic effect. The elucidation of this mechanism of pain and analgesia will lay the theoretical foundation and new ideas for investigating nociceptive signal and screening potential analgesic drugs.