更新于：2024-09-05

SYT2

更新于：2024-09-05

基本信息

别名

synaptotagmin 2、Synaptotagmin II、Synaptotagmin-2

+ [2]

简介

Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties (By similarity). May have a regulatory role in the membrane interactions during trafficking of synaptic vesicles at the active zone of the synapse (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003).

关联

项与 SYT2 相关的药物

Exo-1

靶点

SYT2

作用机制

SYT2抑制剂

在研机构

Exotect, LLC

原研机构

Exotect, LLC

在研适应症

呼吸障碍

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 SYT2 相关的临床结果

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100 项与 SYT2 相关的转化医学

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0 项与 SYT2 相关的专利（医药）

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226

项与 SYT2 相关的文献（医药）

2023-08-11·Pharmacological research

Stabilization of Activated Mast Cells by ORAI1 Inhibitor Suppresses Peanut-Induced Anaphylaxis and Acute Diarrhea.

Article

作者: Gyeongseo Suk ; Do Hoon Kwon ; Axel Roers ; Soman N Abraham ; Hae Woong Choi

Mast cell (MC) activation triggered by immunoglobulin E (IgE)-antigen crosslinking involves intracellular Ca²⁺ influx through the ORAI1 channel, which precedes granule exteriorization and de novo synthesis of mediators. Pharmacologically suppressing MCs via the inhibition of the ORAI1 Ca²⁺ channel may represent a potential strategy for preventing anaphylaxis. This study demonstrated that peanut-induced anaphylaxis in sensitized mice resulted in significant hypothermia and acute diarrhea. Utilizing the Mcpt5cre-DTA mouse model, we demonstrated that this anaphylactic response was mediated by IgE-antigen-induced MC activation. Prophylactic administration of MC suppressors was an effective means of preventing peanut-induced anaphylaxis. In addition, we observed the potent efficacy of an ORAI1 inhibitor in suppressing the FcεRI-mediated response of murine or human MCs, even when administered concurrently or post-allergen exposure. Mechanistically, the ORAI1 inhibitor was found to prevent the association of Synaptotagmin-2 with the SNARE complex. In an in vivo mouse model of peanut-induced anaphylaxis, the administration of the ORAI1 inhibitor after allergen challenge effectively suppressed allergic acute diarrhea and ameliorated anaphylaxis. Therefore, pharmacological intervention of ORAI1 channel inhibition in MCs represents a promising therapeutic avenue for the treatment of peanut-induced anaphylaxis and acute diarrhea in vivo.

2023-05-05·Journal of translational medicine

SYTL2 promotes metastasis of prostate cancer cells by enhancing FSCN1-mediated pseudopodia formation and invasion.

Article

作者: Zean Li ; Yiran Tao ; Ze Gao ; Shirong Peng ; Yiming Lai ; Kaiwen Li ; Xu Chen ; Hai Huang

BACKGROUND:

Metastatic prostate cancer (mPCa) has a poor prognosis with limited treatment options. The high mobility of tumor cells is the key driving characteristic of metastasis. However, the mechanism is complex and far from clarified in PCa. Therefore, it is essential to explore the mechanism of metastasis and discover an intrinsic biomarker for mPCa.

METHODS:

Transcriptome sequencing data and clinicopathologic features of PCa from multifarious public databases were used to identify novel metastatic genes in PCa. The PCa tissue cohort containing 102 formalin-fixed paraffin-embedded (FFPE) samples was used to evaluate the clinicopathologic features of synaptotagmin-like 2 (SYTL2) in PCa. The function of SYTL2 was investigated by migration and invasion assays and a 3D migration model in vitro and a popliteal lymph node metastasis model in vivo. We performed coimmunoprecipitation and protein stability assays to clarify the mechanism of SYTL2.

RESULTS:

We discovered a pseudopodia regulator, SYTL2, which correlated with a higher Gleason score, worse prognosis and higher risk of metastasis. Functional experiments revealed that SYTL2 promoted migration, invasion and lymph node metastasis by increasing pseudopodia formation in vitro and in vivo. Furthermore, SYTL2 induced pseudopodia formation by enhancing the stability of fascin actin-bundling protein 1 (FSCN1) by binding and inhibiting the proteasome degradation pathway. Targeting FSCN1 enabled rescue and reversal of the oncogenic effect of SYTL2.

CONCLUSIONS:

Overall, our study established an FSCN1-dependent mechanism by which SYTL2 regulates the mobility of PCa cells. We also found that the SYTL2-FSCN1-pseudopodia axis may serve as a pharmacological and novel target for treating mPCa.

2023-03-31·Cerebral cortex (New York, N.Y. : 1991)

Normal connectivity of thalamorecipient networks in barrel equivalents of the reeler cortex.

Article

作者: Anouk J M Meeuwissen ; Martin Möck ; Jochen F Staiger ; Julien Guy

The reeler mouse mutant has long served as a primary model to study the development of cortical layers, which is governed by the extracellular glycoprotein reelin secreted by Cajal-Retzius cells. Because layers organize local and long-range circuits for sensory processing, we investigated whether intracortical connectivity is compromised by reelin deficiency in this model. We generated a transgenic reeler mutant (we used both sexes), in which layer 4-fated spiny stellate neurons are labeled with tdTomato and applied slice electrophysiology and immunohistochemistry with synaptotagmin-2 to study the circuitry between the major thalamorecipient cell types, namely excitatory spiny stellate and inhibitory fast-spiking (putative basket) cells. In the reeler mouse, spiny stellate cells are clustered into barrel equivalents. In these clusters, we found that intrinsic physiology, connectivity, and morphology of spiny stellate and fast-spiking, putative basket cells does not significantly differ between reeler and controls. Properties of unitary connections, including connection probability, were very comparable in excitatory cell pairs and spiny stellate/fast-spiking cell pairs, suggesting an intact excitation-inhibition balance at the first stage of cortical sensory information processing. Together with previous findings, this suggests that thalamorecipient circuitry in the barrel cortex develops and functions independently of proper cortical lamination and postnatal reelin signaling.

项与 SYT2 相关的新闻（医药）

2022-04-06

·新浪医药新闻

造福呼吸道疾病患者！全新疗法可避免致命黏液堵住呼吸道

哮喘、慢性肺阻塞、肺囊性纤维化以及肺癌，众多肺部疾病影响着全世界数亿人。患有这些肺部疾病的人会遇到一个重大问题：呼吸道产生过量黏液。浓稠的黏液堵住呼吸道，引起一系列症状，轻则咳嗽，重则肺功能严重下降。好消息是，根据近日发表于顶尖学术期刊《自然》的一篇研究论文，科学家们现在终于开发出了一种药物，专门阻止呼吸道过量分泌黏液，有望为黏液堵塞呼吸道的患者改善生活。研究团队指出，这是第一种专门缓解黏液病理性分泌的化合物，并不会影响黏液的正常分泌。对于健康人来说，黏液97%都是水，只有少量的黏蛋白（mucin）。鼻子、喉咙、支气管和肺小气道表面的上皮细胞分泌出的黏蛋白，吸收水分并形成一层薄薄的保护膜，既是润滑剂也是屏障，还可以裹紧病原体，在你打喷嚏或是咳嗽时由呼吸道上皮细胞的纤毛将病原体驱除出去。但是在阻塞性肺炎等疾病中，持续存在的炎症状态刺激黏蛋白过度分泌。突然分泌出来的大量黏蛋白吸收不到足够的水分，变得浓稠，凝结的痰块咳不出来，堵塞呼吸道。在过去二十多年的工作中，研究黏蛋白分泌机制的科学家们从神经科学家那里发现了一个令人意外的“巧合”：肺和大脑有着类似的分泌机制。简单来说，神经细胞在突触部位释放神经递质，接到钙信号后，通过突触结合蛋白（synaptotagmin）等关键分子，刺激一种叫“囊泡”的结构，使其与细胞膜融合，释放出囊泡里的神经递质。气道分泌黏蛋白涉及的关键基因和蛋白质与此不无相似之处，炎症也会触发分泌细胞内的钙信号，由突触结合蛋白作用于囊泡，只不过释放出来的不是神经递质而是黏蛋白。 “我们弄清楚了分泌机制，知道了所有的主要参与者，”Dickey教授说。“当我们了解各部分如何协同工作后，就确定了突触结合蛋白Syt2是阻断黏蛋白分泌的最佳靶点，因为它只有在高水平的刺激下才会被激活。也就是说，阻断Syt2的活性理论上可以防止黏蛋白突然大量释放，而不会有碍于基本的缓慢、稳定的黏蛋白分泌。” ▲呼吸道上皮细胞分泌黏蛋白涉及囊泡在钙信号刺激下与细胞膜融合的机制，突触结合蛋白Syt2可以作为减少多余黏液的靶点（图片来源：参考资料[2]）在这项研究中，多个机构合作开展的工作利用不同的临床前模型验证了，Syt2是一种可行的治疗靶点。例如缺少Syt2的基因工程小鼠，可以在炎症环境下减少黏蛋白的过量分泌。对照组的野生型小鼠在这种环境下通常会出现类似哮喘的过敏反应，相比之下，突变小鼠分泌的黏蛋白足以减少70%，堵住气道的痰块只有对照组的四分之一。基于这一机制，研究团队设计了一种可以结合在Syt2上的多肽SP9，由它来阻止Syt2与其协同作用的蛋白复合物对钙信号作为响应。研究人员对这种多肽的氨基酸进行了专门的化学修饰，合成出所谓的订书肽（stapled peptide），以便稳定其结构并保证有效地结合蛋白质靶标。这篇论文的第一作者赖颖博士与同事们通过实验验证，SP9可以成功阻碍钙信号触发的膜融合，避免囊泡释放黏蛋白。 ▲用工程肽SP9（亮黄色所示）干扰突触结合蛋白（橙色）与突触融合过程中必需的蛋白复合物（蓝、红、绿色所示）相互作用，起到抑制黏蛋白分泌的作用（图片来源：参考资料[3]；Illustration：Eric D. Smith）接下来，研究团队进一步对SP9做了改造，将其与另一种能够穿透细胞膜的肽PEN绑定在一起，帮助SP9成功进入分泌细胞内发挥作用。在培养的人体上皮细胞中，这种偶联物的效果得到了验证。随后，研究团队将PEN-SP9开发为雾化剂，并在小鼠实验中确认，这种药物可以帮助动物避免过多的黏液堵住呼吸道，并且不影响黏蛋白正常分泌。该研究的负责人之一、斯坦福大学的Axel Brunger教授表示，他们还将继续优化SP9，希望在未来几年内进入临床试验，尽快造福患者。参考资料： [1] Ying Lai et al., (2022) Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides. Nature. Doi: https://doi.org/10.1038/s41586-022-04543-1 [2] Irina Gitlin & John V. Fahy (2022) Mucus secretion blocked at its source in the lungs. Nature. Doi: https://doi.org/10.1038/d41586-022-00700-8 [3] Novel therapy could help people with asthma, COPD, cystic fibrosis and cancer-related lung disease. Retrieved Mar. 29, 2022 from https://www.eurekalert.org/news-releases/947325 [4] Scientists develop compound that could treat asthma, other mucus-induced lung diseases. Retrieved Mar. 29, 2022 from https://med.stanford.edu/news/all-news/2022/03/excessive-mucus-secretion-blocking-compound.html 内容来源于网络，如有侵权，请联系删除，谢谢。