TRPM8抑制と無感化に関する構造的洞察
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
まとめ
TRPM8イオンチャネルの構造的な洞察は,冷たい感覚と過敏性を理解するために重要な閉じた状態と無感覚状態を明らかにします. この研究で TRPM8 について説明します.
科学分野:
- 構造生物学
- イオンチャンネル生理学
- 神経科学
背景:
- 臨時受容体潜在メラスタチン8 (TRPM8) イオンチャネルは環境の寒さを検知する.
- TRPM8は病理的な感冒過敏症の治療における重要な標的である.
- TRPM8の構造と機能を理解することは,治療開発に不可欠です.
研究 の 目的:
- TRPM8ゲーティングと無感化の構造的基礎を明らかにする.
- TRPM8のリガンド結合ポケットとイオン浸透経路を特徴付ける.
- カルシウム媒介によるTRPM8無敏感化のメカニズムを明らかにする.
主な方法:
- クリオ電子顕微鏡 (cryo-EM) でTRPM8の構造を決定する.
- リガンドフリー,抗体結合,およびカルシウム結合のTRPM8状態の分析
- イオン浸透経路と脂質相互作用の構造的特徴.
主要な成果:
- TRPM8の非導体状態を 明らかにした.
- 多様な薬物の構造を収納する 柔軟なリガンド結合ポケットを特定しました
- 直接カルシウム結合が示され,刺激による無敏感化を媒介する.
- S4からS5のリンクとドメインの位置づけに 重要な変化が観察されました
結論:
- TRPM8の形状の変化は,その寒さ感知および無感知化メカニズムを支えている.
- 柔軟性のあるリガンド結合ポケットは 薬物設計の機会を提供します
- 他のTRPチャネルに適用できる新しいTRPM8モデルの提案がなされている.
関連する概念動画
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