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TPCs:从植物到人类

Yvonne Eileen Klingl^1,2, Arnas Petrauskas^1,2, Dawid Jaślan¹

¹Walther-Straub Institute of Pharmacology and Toxicology, Ludwig Maximilian University Munich, Munich, Germany.

Physiological reviews

|April 8, 2025

概括

双孔通道 (TPC) 对于细胞信号传递和离子运输至关重要. 最近的研究和解了关于TPC激活的争议,揭示了依赖联体的选择性和疾病中的作用,突出了它们的治疗潜力.

科学领域:

分子生物学分子生物学
细胞生理学细胞生理学
离子通道功能的功能

背景情况:

两孔通道 (TPC) 最初在植物中被发现,后来在哺乳动物中被发现,早期研究讨论了它们作为Ca2+或Na+通道的功能.
关于尼古丁酸腺因二核酸 (NAADP) 或酸丁-3,5-双酸 (PI(3,5) P2) 激活哺乳动物TPC的相互矛盾的发现引起了重大的科学争议.
TPCs涉及各种细胞过程,包括自,外,内和细胞内贩运,对脂肪肝,传染病,癌症和神经退行性疾病等疾病有影响.

研究的目的:

调和有关哺乳动物TPC激活机制和通道选择性的相互矛盾的发现.
探索TPC在各种生理和病理生理过程中的作用,包括溶酶体储存疾病.
审查TPC结构,功能以及它们作为药物点潜力的最新进展.

主要方法:

利用脂性小分子激动剂来模仿NAADP和PI的3,5) P2激活模式的TPC2.
结合了结构证据来阐明TPC2的依赖联体的离子选择性.
审查了有关TPC功能,生理学和病理生理学的现有文献,重点关注植物和哺乳动物系统.

主要成果:

TPC2对Ca²⁺与Na⁺ (N型与P型激活) 具有依赖于连接体的选择性,和解了之前的争议.
发现NAADP结合蛋白 (木星微管相关同类2蛋白和Lsm12) 支持对NAADP激活的辅助蛋白的要求.
TPC功能障碍与多种病理有关,包括脂肪肝疾病,传染病 (埃博拉,COVID-19),癌症和神经退行性溶酶体储存疾病的贩运受损,其中P型激活显示出治疗前景.

结论:

TPCs的激活和功能比以前想象的要复杂得多,涉及依赖连接体的选择性和辅助蛋白相互作用.
TPCs在细胞平衡中起着至关重要的作用,并与广泛的人类疾病有关,这强调了它们的生理意义.
针对TPCs为各种疾病提供了一个有前途的治疗策略,包括溶酶体储存疾病,传染病和癌症.

关键词:

在TPC中,TPC是TPC.TPCN1 一个问题.在TPCN2中使用.这是一种 lysosomal lysosomal.

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