精细排序的细胞内域内含一个全位,以调节P2X3受体的生理病理功能
Yi-Yu Lin1, Yan Lu1, Chun-Yun Li1
1School of Basic Medicine and Clinical Pharmacy, and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Nature communications
|September 3, 2024
概括
对于疼痛和炎症至关重要的P2X3受体的细胞内域具有结构化的阿波状态. 这种结构允许全调制,影响P2X3通道功能,并提供新的治疗点.
科学领域:
- 离子通道生物物理 离子通道生物物理
- 分子药理学分子药理学
- 神经科学是一个神经科学.
背景情况:
- P2X受体是由ATP激活的联结离子通道,参与炎症,疼痛和免疫反应.
- 虽然细胞外P2X受体结构得到保存,但细胞内域 (ICD) 结构在apo状态是矛盾的,使其功能不清楚.
- 了解P2X3受体ICD对于阐明它在生理和病理过程中的作用至关重要.
研究的目的:
- 研究P2X3受体细胞内域 (ICD) 在其阿波状态中的结构和功能作用.
- 在P2X3 ICD中识别调节通道活性和生理作用的全位.
- 发现P2X3受体功能的新型调节剂.
主要方法:
- 协价占用和工程二硫化物键探测ICD结构和动态.
- 电压的度测量用于评估通道激活和协调运动.
- 使用P2rx3淘汰赛小鼠进行体内研究,以评估ICD在疼痛感知中的作用.
主要成果:
- P2X3受体ICD在apo状态下采用了一个有序的,不那么紧张的形状,与一个无序的结构不同.
- 该ICD经历了与跨膜领域协调的运动,促进了通道激活.
- 发现了一种新的P2X3增强剂PSFL77,该增强剂向ICD的1α3β域内的全位.
- 在野生型小鼠中,PSFL77调节了疼痛感知,但在P2rx3淘汰小鼠中没有.
结论:
- P2X3受体ICD在apo状态下被命令,使P2X3信号的全调制成为可能.
- P2X3 ICD的1α3β域代表了对受体功能和疼痛调制至关重要的可调节区域.
- 针对P2X3 ICD提供了一个有前途的策略,用于开发用于疼痛和炎症条件的新疗法.
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