TPCN2

更新于：2025-05-07

基本信息

别名

TPC2、TPCN2、Two pore calcium channel protein 2

+ [2]

简介

Intracellular channel initially characterized as a non-selective Ca(2+)-permeable channel activated by NAADP (nicotinic acid adenine dinucleotide phosphate), it is also a highly-selective Na(+) channel activated directly by PI(3,5)P2 (phosphatidylinositol 3,5-bisphosphate) (PubMed:19387438, PubMed:19620632, PubMed:20880839, PubMed:23063126, PubMed:23394946, PubMed:24502975, PubMed:24776928, PubMed:30860481, PubMed:31825310, PubMed:32167471). Localizes to the lysosomal and late endosome membranes where it regulates organellar membrane excitability, membrane trafficking, and pH homeostasis. Is associated with a plethora of physiological processes, including mTOR-dependent nutrient sensing, skin pigmentation and autophagy (PubMed:18488028, PubMed:23394946, PubMed:32167471). Ion selectivity is not fixed but rather agonist-dependent and under defined ionic conditions, can be readily activated by both NAADP and PI(3,5)P2 (PubMed:24502975, PubMed:31825310, PubMed:32167471). As calcium channel, it increases the pH in the lysosomal lumen, as sodium channel, it promotes lysosomal exocytosis (PubMed:31825310, PubMed:32167471). Plays a crucial role in endolysosomal trafficking in the endolysosomal degradation pathway and is potentially involved in the homeostatic control of many macromolecules and cell metabolites (By similarity) (PubMed:18488028, PubMed:19387438, PubMed:19620632, PubMed:20880839, PubMed:23063126, PubMed:23394946, PubMed:24502975, PubMed:24776928, PubMed:31825310, PubMed:32167471, PubMed:32679067). Also expressed in melanosomes of pigmented cells where mediates a Ca(2+) channel and/or PI(3,5)P2-activated melanosomal Na(+) channel to acidify pH and inhibit tyrosinase activity required for melanogenesis and pigmentation (PubMed:27140606). Unlike the voltage-dependent TPCN1, TPCN2 is voltage independent and can be activated solely by PI(3,5)P2 binding. In contrast, PI(4,5)P2, PI(3,4)P2, PI(3)P and PI(5)P have no obvious effect on channel activation (PubMed:30860481). (Microbial infection) During Ebola virus (EBOV) infection, controls the movement of endosomes containing virus particles and is required by EBOV to escape from the endosomal network into the cell cytoplasm. (Microbial infection) Required for cell entry of coronaviruses SARS-CoV and SARS-CoV-2, as well as human coronavirus EMC (HCoV-EMC), by endocytosis.

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100 项与 TPCN2 相关的临床结果

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0 项与 TPCN2 相关的专利（医药）

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213

项与 TPCN2 相关的文献（医药）

2025-07-01·Physiological Reviews

TPCs: FROM PLANT TO HUMAN

Review

作者: Grimm, Christian ; Klingl, Yvonne Eileen ; Jaślan, Dawid ; Petrauskas, Arnas

In 2005, the Arabidopsis thaliana two-pore channel TPC1 channel was identified as a vacuolar Ca2+-release channel. In 2009, three independent groups published studies on mammalian TPCs as nicotinic acid adenine dinucleotide phosphate (NAADP)-activated endolysosomal Ca2+ release channels, results that were eventually challenged by two other groups, claiming mammalian TPCs to be phosphatidylinositol-3,5-bisphosphate [PI(3,5)P2]-activated Na+ channels. By now this dispute seems to have been largely reconciled. Lipophilic small molecule agonists of TPC2, mimicking either the NAADP or the PI(3,5)P2 mode of channel activation, revealed, together with structural evidence, that TPC2 can change its selectivity for Ca2+ versus Na+ in a ligand-dependent fashion (N- vs. P-type activation). Furthermore, the NAADP-binding proteins Jupiter microtubule-associated homolog 2 protein (JPT2) and Lsm12 were discovered, corroborating the hypothesis that NAADP activation of TPCs only works in the presence of these auxiliary NAADP-binding proteins. Pathophysiologically, loss or gain of function of TPCs has effects on autophagy, exocytosis, endocytosis, and intracellular trafficking, e.g., LDL cholesterol trafficking leading to fatty liver disease or viral and bacterial toxin trafficking, corroborating the roles of TPCs in infectious diseases such as Ebola or COVID-19. Defects in the trafficking of epidermal growth factor receptor and β1-integrin suggested roles in cancer. In neurodegenerative lysosomal storage disease models, P-type activation of TPC2 was found to have beneficial effects on both in vitro and in vivo hallmarks of Niemann-Pick disease type C1, Batten disease, and mucolipidosis type IV. Here, we cover the latest on the structure, function, physiology, and pathophysiology of these channels with a focus initially on plants followed by mammalian TPCs, and we discuss their potential as drug targets, including currently available pharmacology.

2025-06-02·Journal of Cell Biology

Lysosomal TPC2 channels disrupt Ca2+ entry and dopaminergic function in models of LRRK2-Parkinson’s disease

Article

作者: Gregori, Martina ; Allen, Robert ; Schapira, Anthony H.V. ; Pereira, Gustavo J.S. ; Lee, Chiao-Yin ; Hasan, Gaiti ; Cai, Xinjiang ; Keller, Marco ; Patel, Sandip ; Chau, Kai-Yin ; Sweeney, Sean T. ; West, Nicholas ; Harvey, Kirsten ; Gegg, Matthew E. ; Grimm, Christian ; Bracher, Franz ; Lei, Si Hang ; Bostock, Matthew P. ; Bolsover, Stephen R.

Parkinson’s disease results from degeneration of dopaminergic neurons in the midbrain, but the underlying mechanisms are unclear. Here, we identify novel crosstalk between depolarization-induced entry of Ca2+ and lysosomal cation release in maintaining dopaminergic neuronal function. The common disease-causing G2019S mutation in LRRK2 selectively exaggerated Ca2+ entry in vitro. Chemical and molecular strategies inhibiting the lysosomal ion channel TPC2 reversed this. Using Drosophila, which lack TPCs, we show that the expression of human TPC2 phenocopied LRRK2 G2019S in perturbing dopaminergic-dependent vision and movement in vivo. Mechanistically, dysfunction required an intact pore, correct subcellular targeting and Rab interactivity of TPC2. Reducing Ca2+ permeability with a novel biased TPC2 agonist corrected deviant Ca2+ entry and behavioral defects. Thus, both inhibition and select activation of TPC2 are beneficial. Functional coupling between lysosomal cation release and Ca2+ influx emerges as a potential druggable node in Parkinson’s disease.

2025-05-05·Journal of General Physiology

In silico characterization of the gating and selectivity mechanism of the human TPC2 cation channel

Article

作者: Şahin, Alp Tegin ; Zachariae, Ulrich

Two-pore channels (TPCs) are twofold symmetric endolysosomal cation channels forming important drug targets, especially for antiviral drugs. They are activated by calcium, ligand binding, and membrane voltage, and to date, they are the only ion channels shown to alter their ion selectivity depending on the type of bound ligand. However, despite their importance, ligand activation of TPCs and the molecular mechanisms underlying their ion selectivity are still poorly understood. Here, we set out to elucidate the mechanistic basis for the ion selectivity of human TPC2 (hTPC2) and the molecular mechanism of ligand-induced channel activation by the lipid PI(3,5)P2. We performed all-atom in silico electrophysiology simulations to study Na+ and Ca2+ permeation across full-length hTPC2 on the timescale of ion conduction and investigated the conformational changes induced by the presence or absence of bound PI(3,5)P2. Our findings reveal that hTPC2 adopts distinct conformations depending on the presence of PI(3,5)P2 and elucidate the allosteric transition pathways between these structures. Additionally, we examined the permeation mechanism, solvation states, and binding sites of ions during ion permeation through the pore. The results of our simulations explain the experimental observation that hTPC2 is more selective for Na+ over Ca2+ ions in the presence of PI(3,5)P2via a multilayer selectivity mechanism. Importantly, mutations in the selectivity filter region of hTPC2 maintain cation conduction but change the ion selectivity of hTPC2 drastically.

项与 TPCN2 相关的新闻（医药）

2024-11-28

·生物谷

Nat Commun：新研究揭示黑色素瘤产生的关键机制

研究结果表明，Rab7a通过放大TPC2的活性，在调节肿瘤生长方面发挥了关键作用。在一项新的研究中，来自德国慕尼黑大学的研究人员发现了一种关键蛋白与溶酶体内离子通道之间的相互作用如何促进皮肤癌肿瘤的产生。相关研究结果于2024年11月19日发表在Nature Communications期刊上，论文标题为“Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis”。由称为黑色素细胞（melanocyte）的色素生成细胞引发的黑色素瘤是最致命的皮肤癌。导致黑色素瘤的一个主要原因是过度暴露于阳光或其他来源的紫外线，毕竟紫外线会引发突变，促进肿瘤的形成。在慕尼黑大学药剂学者Christian Grimm 教授和Karin Bartel 博士的领导下，这些作者如今对黑色素瘤发生的分子机制进行了研究。他们证实，两种蛋白——离子通道 TPC2 和 Rab7a 酶之间的相互作用发挥了决定性作用，因为它们促进了黑色素瘤的生长和转移。现有研究已表明，离子通道TPC2的某些活性增强突变与白皙的皮肤、金色的头发和白化病有关。这些特征使人们特别容易患上黑色素瘤，因为他们的皮肤对有害紫外线辐射的防护能力较弱。相反，TPC2 的缺失与黑色素瘤风险的降低有关。这种离子通道控制着内溶酶体中重要蛋白的分解，从而影响着调节肿瘤生长的信号通路。影响肿瘤进展的分子途径与 TPC2 蛋白一样，Rab7a 蛋白也是内溶酶体系统的重要调节因子。此外，早期的蛋白质组分析表明，Rab7a 是 TPC2 的潜在相互作用搭档。作者利用内溶酶体膜片钳电生理学和荧光显微镜测量溶酶体钙释放等现代方法，确定了 Rab7a 和 TPC2 在功能水平上确实存在相互作用，从而促进了黑色素瘤细胞的生长和侵袭性。相反，药物抑制 Rab7a 会降低 TPC2 的活性，从而降低黑色素瘤的生长。 Rab7a在黑色素瘤与非黑色素瘤癌细胞中的表达，与TPC2表达的相关性，以及Rab7a与TPC2的相互作用 Grimm说，“我们的研究结果表明，Rab7a通过放大TPC2的活性，在调节肿瘤生长方面发挥了关键作用。具体来说，Rab7a 对 TPC2 的激活会降低某种蛋白的水平。这种蛋白能提高转录因子的稳定性，而转录因子是黑色素细胞和黑色素瘤的关键调节因子，能促进它们的增殖和存活。” 他们指出，一个特别值得注意的发现是，Rab7a 和 TPC2 的相互作用可以在体内得到证实。在没有Rab7a或TPC2的黑色素瘤细胞小鼠模型中，他们发现肿瘤的大小和转移都大大减少。 Grimm总结说，“Rab7a和TPC2之间的相互作用可能为开发针对促进黑色素瘤生长和转移的特定信号通路的新治疗策略铺平道路。”（生物谷Bioon.com）参考资料： Carla Abrahamian et al. Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis. Nature Communications, 2024, doi:10.1038/s41467-024-54324-9.

临床研究临床终止诊断试剂

2021-05-02

·药事纵横

新冠病毒--药物靶点一览！

‍ 注：因水平有限，错误不可避免，欢迎留言指出。 ‍ 目前全球疫情有2个特点，一方面，中美欧等国家地区积极进行新冠疫苗的接种，另一方面，印度以及巴西，疫情依然严重，据统计，连续多日，印度单日新增确诊感染超过30万人。如何预防新冠病毒、积极治疗感染患者，对全球公共卫生依然是重大挑战。来源：APE图库当前对新冠病毒的结构已经了解，对病毒传染机制也有了了解，基于病毒结构和传染机制，全球都在积极开展药物研发。本文对国外文献进行进行编译，介绍下病毒结构、感染机制以及药物靶点等。病毒结构当前对新冠病毒的结构已经了解，对病毒传染机制也有了了解，基于病毒结构和传染机制，全球都在积极开展药物研发。本文对国外文献进行进行编译，介绍下病毒结构、感染机制以及药物靶点等。感染机制当前对新冠病毒的结构已经了解，对病毒传染机制也有了了解，基于病毒结构和传染机制，全球都在积极开展药物研发。本文对国外文献进行进行编译，介绍下病毒结构、感染机制以及药物靶点等。药物靶点当前对新冠病毒的结构已经了解，对病毒传染机制也有了了解，基于病毒结构和传染机制，全球都在积极开展药物研发。本文对国外文献进行进行编译，介绍下病毒结构、感染机制以及药物靶点等。 Subramanian Boopathi等撰文介绍了新冠病毒结构，与其他冠状病毒结构类似，新冠病毒也主要包括2部分：外层包膜和内层核衣壳。图：新冠病毒结构示意图来源：J Biomol Struct Dyn. 2020 Apr 30;1-10. doi: 10.1080/07391102.2020.1758788 Carmen Gil等撰文总结了新冠病毒感染过程，第一步：病毒刺突糖蛋白（S蛋白）与宿主血管紧张素转化酶2（ACE2）受体的结合；第二步，宿主跨膜丝氨酸蛋白酶2（ T MPRSS2 ）对病毒刺突糖蛋白的切割融合；第三步，病毒融合进宿主细胞膜。图：新冠病毒感染途径来源：J. Med. Chem. 2020, 63, 12359−12386. 除了与质膜直接融合之外，Wang及其同事根据对SARS-CoV的观察，将胞吞途径确立为另一种进入宿主途径。 Ou, X等研究表明胞吞途径是SARS-CoV-2进入宿主细胞的首选途径。 S蛋白的蛋白酶激活对于冠状病毒的进入宿主细胞至关重要。溶酶体组织蛋白酶对于SARS和MERS-CoV通过胞吞途径进入宿主是必需的。一旦病毒进入宿主细胞，它就会被分解以释放核衣壳和病毒基因组。原则上，在寻找SARS-CoV-2的治疗方案时，与病毒复制和宿主细胞控制有关的所有病毒酶和蛋白质都是潜在的成药靶点。基于病毒的靶点结构蛋白质Structural Proteins. 刺突糖蛋白 spike (S) glycoprotein 、包膜蛋白 envelope (E) protein 、膜蛋白 membrane (M) protein 和核衣壳蛋白 nucleocapsid (N) protein。刺突糖蛋白（S蛋白）在病毒的发病机理和器官嗜性中起重要作用，通过受体识别和膜融合作用引起病毒感染；包膜蛋白（E蛋白）是结构蛋白中最小的，但在病毒的组装、出芽、包膜形成和致病性方面起关键作用；膜蛋白（M蛋白）的主要功能是由于其膜弯曲特性而促进病毒装配；核衣壳蛋白（N蛋白）是组装病毒RNA基因组的多功能蛋白。非结构蛋白质Non-structural Proteins (nsps). 与其他冠状病毒一样，SARS-CoV-2具有16中高度保守的非结构蛋白质，并表现出不同的功能，包括上述4种蛋白的形成。高度保守的与其他冠状病毒一样，SARS-CoV-2具有16中高度保守的非结构蛋白质，并表现出不同的功能，包括上述4种蛋白的形成。瑞德西韦的可能靶点就是非结构蛋白质(nsps)中RNA依赖性RNA聚合酶（RdRp）。来源： APE图库基于宿主的靶点血管紧张素 | 转换酶2（ACE2）受体Angiotensin I Converting Enzyme 2 (ACE2) Receptor 冠状病毒的感染主要是由于病毒与宿主细胞表面的不同受体结合而产生的。在SARS-CoV-2中，最近已确认ACE2是主要的病毒受体。因此，抑制或调节ACE2代表了基于宿主的SARS-CoV-2治疗策略之一。跨膜丝氨酸蛋白酶2（TMPRSS2）Transmembrane Serine Protease 2 (TMPRSS2) 不同的宿主蛋白酶可以激活病毒，便于病毒与宿主细胞膜融合。宿主细胞表面跨膜丝氨酸蛋白酶2（TMPRSS2）激活高致病性人冠状病毒SARS-CoV和MERS-CoV的S蛋白。TMPRSS2在人体的胃肠道，泌尿生殖道和呼吸道上皮中高表达。其他蛋白酶（例如内体组织蛋白酶）相比，TMPRSS2切割S蛋白更适合于冠状病毒感染。弗林/Furin 研究发现，SARS-CoV-2的S蛋白中有一个“弗林蛋白酶样切割位点”（FCS），可以解释该病毒的高致病性。组织蛋白酶L/Cathepsin L 通过裂解蛋白酶激活SARS-CoV-2的S蛋白是病毒感染的关键步骤。不同的溶酶体组织蛋白酶与通过胞吞作用进入人类冠状病毒有关。有研究表明仅组织蛋白酶L参与了SARS-CoV-2内吞作用。衔接蛋白相关激酶1（AAK1）和细胞周期蛋白G相关激酶（GAK）Adaptor-Associated Kinase 1 (AAK1) and Cyclin G-Associated Kinase (GAK) SARS-CoVs的主要进入途径是受体介导的胞吞作用。 AAK1和GAK是宿主丝氨酸-苏氨酸蛋白激酶，可调节多种无关RNA病毒（例如狂犬病，埃博拉病毒，登革热或丙型肝炎病毒）的进入，组装和释放过程中的细胞内病毒运输。磷酸肌醇3-磷酸5-激酶（PIKfyve） Phosphatidylinositol 3-Phosphate 5-Kinase(PIKfyve) 在胞吞作用中，调节内体成熟动态过程的分子之一是磷脂酰肌醇-3,5-双磷酸酯（PI（3,5）P2）。这种磷脂是由PIKfyve在核内体晚期合成的，PIKfyve是一种具有脂类和蛋白激酶活性的酶。PIKfyve在胞吞途径相关的几个转运过程起着关键作用。双孔通道（TPC2）/Two-Pore Channel (TPC2) 在溶酶体系统的不同通道之间，双孔通道（TPC1-3）调节跨细胞膜的钠离子和钙离子的电导。它们是电位-门控通道，TPC2由PI（3,5）P2这种磷酸肌醇激活。这些参与溶酶体运输和埃博拉进入宿主细胞的调节。电位-门控在溶酶体系统的不同通道之间，双孔通道（TPC1-3）调节跨细胞膜的钠离子和钙离子的电导。它们是电位-门控通道，TPC2由PI（3,5）P2这种磷酸肌醇激活。这些参与溶酶体运输和埃博拉进入宿主细胞的调节。基于上述靶点可以开展各种抗病毒药物的开发。期待有特效药被开发出来参考资料 --Subramanian Boopathi, Adolfo B Poma, Ponmalai Kolandaivel, Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment. J Biomol Struct Dyn. 2020 Apr 30;1-10. doi: 10.1080/07391102.2020.1758788. --Carmen Gil, Tiziana Ginex, Ines Maestro, etc. COVID-19: Drug Targets and Potential Treatments. J. Med. Chem. 2020, 63, 12359−12386.--Wang, H.; Yang, P.; Liu, K.; Guo, F.; Zhang, Y.; Zhang, G.; Jiang, C. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008, 18 (2), 290−301. --Carmen Gil, Tiziana Ginex, Ines Maestro, etc. COVID-19: Drug Targets and Potential Treatments. J. Med. Chem. 2020, 63, 12359−12386.--Wang, H.; Yang, P.; Liu, K.; Guo, F.; Zhang, Y.; Zhang, G.; Jiang, C. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008, 18 (2), 290−301. --Ou, X.; Liu, Y.; Lei, X.; Li, P.; Mi, D.; Ren, L.; Guo, L.; Guo, R.; Chen, T.; Hu, J.; Xiang, Z.; Mu, Z.; Chen, X.; Chen, J.; Hu, K.; Jin, Q.; Wang, J.; Qian, Z. Characterization of spike glycoprotein of SARSCoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat. Commun. 2020, 11 (1), 1620. --其他参考文献药事纵横投稿须知：稿费已上调，欢迎投稿各位朋友好，觉得本文对您有帮助，请随手点一下下方的在看，以便让你的朋友也能看到哦。