对TRPM8抑制和脱敏的结构性见解
Melinda M Diver1, Yifan Cheng2,3, David Julius4
1Department of Physiology, University of California, San Francisco, San Francisco, CA 94143, USA.
Science (New York, N.Y.)
|September 7, 2019
概括
对TRPM8离子通道的结构洞察力揭示了封闭和无敏状态,这对于理解感冒和过敏至关重要. 这项研究澄清了TRPM8的TRPM8.
科学领域:
- 结构生物学 结构生物学
- 离子通道生理学 离子通道生理学
- 神经科学是一个神经科学.
背景情况:
- 瞬态受体潜力拉斯8 (TRPM8) 离子通道检测到环境的寒冷.
- TRPM8是治疗病态感冒过敏症的关键目标.
- 了解TRPM8的结构和功能对于治疗开发至关重要.
研究的目的:
- 阐明TRPM8关门和脱敏的结构基础.
- 为了描述TRPM8的连接体结合口袋和离子透通路.
- 为了揭示介导TRPM8脱敏的机制.
主要方法:
- 低温电子显微镜 (cryo-EM) 用于确定TRPM8结构.
- 分析无联体,抗体结合和结合的TRPM8状态.
- 离子透通路和脂质相互作用的结构特征.
主要成果:
- 揭示了TRPM8.的截然不同的封闭和脱敏的非导电状态.
- 鉴定了一种灵活的带结合口袋,可以容纳各种药物结构.
- 已证明直接结合可以调解刺激引起的无敏化.
- 在S4-S5链接器和域定位中观察到显著的重排.
结论:
- TRPM8的形状变化是其冷感应和脱敏机制的基础.
- 可形的带结合口袋为药物设计提供了机会.
- 提出了一种TRPM8调制的新型模型,可能适用于其他TRP通道.
相关概念视频
01:12GPCR Desensitization
8.0K
G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
8.0K
01:20Desensitization and Tachyphylaxis
3.0K
Tachyphylaxis is described as a rapid decrease in response to a drug after repeated or continuous administration of the same drug dose. It is a phenomenon where the body becomes less responsive to a particular substance or intervention over time, requiring higher doses or stronger interventions to achieve the same effect. It results from adaptive changes in the body's receptors, signaling pathways, or physiological processes that occur in response to prolonged exposure to a stimulus.
3.0K
08:03Advanced Self-Healing Asphalt Reinforced by Graphene Structures: An Atomistic Insight
5.6K
Graphene-modified asphalt nanocomposite has shown an advanced self-healing ability compared to pure asphalt. In this protocol, molecular dynamics simulations have been applied in order to understand the role of graphene in the self-healing process and to explore the self-healing mechanism of asphalt components from the atomistic...
5.6K
06:43Desensitization and Recovery of Crayfish Photoreceptors Upon Delivery of a Light Stimulus
7.0K
A protocol for the study of desensitization and sensitivity recovery of crayfish photoreceptors as a function of circadian time is...
7.0K
00:46Feedback Inhibition
56.9K
Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
56.9K
02:54Intracerebroventricular Treatment with Resiniferatoxin for TRPV1 Desensitization in the Mouse Brain
342
Source: Fukushima, A., et al. Intracerebroventricular Treatment with Resiniferatoxin and Pain Tests in Mice. J. Vis. Exp. (2020)This video demonstrates the procedure for intracerebroventricular injection of resiniferatoxin in mice to desensitize the TRPV1 receptors in the...
342