摘要
背景:存储操作的钙进入(SOCE),主要由Orai1和基质相互作用分子1(STIM1)介导,是一种主要的Ca2 +流入途径,与人类疾病有关,包括肌病,癫痫,免疫缺陷和癌症。尽管最近解剖SOCE活化的分子机制的快速进展,但是针对功能失调的SOCE的治疗方法的发展显着滞后,部分原因是由于缺乏更具体的药理学工具和对目前可用的SOCE改性剂的理解不足,包括新发现的SOCE抑制剂,洋地黄毒苷。 目的和方法:利用Ca2 +成像和药理学工具,我们旨在通过定义它如何影响Orai1对SOCE发挥其抑制作用来系统地描述洋地黄毒苷的作用机制。 结果:洋地黄毒苷的SOCE抑制功能依赖于野生型Orai1的S27-S30残基。将洋地黄毒苷与STIM1-预结合的Orai1或组成型活性突变体Orai1-ANSGA孵育8小时,其抑制作用不再依赖于S27-S30残基。相反,抑制可能涉及Orai1通道的孔区域,因为孔区域的V102C突变体将大大减少或消除对预活化的Orai1的抑制。 结论:我们的研究确定了两个对Orai1通道抑制至关重要的区域,为将来设计SOCE抑制剂提供了宝贵的热点。
关键词: 钙信号,荧光成像,洋地黄,SOCE,Orai 1,磷酸化。
Current Molecular Medicine
Title:Digitoxin Suppresses Store Operated Calcium Entry by Modulating Phosphorylation and the Pore Region of Orai1
Volume: 18 Issue: 6
关键词: 钙信号,荧光成像,洋地黄,SOCE,Orai 1,磷酸化。
摘要: Background: Store-operated calcium entry (SOCE), primarily mediated by Orai1 and stromal interaction molecule 1 (STIM1), is a major Ca2+ influx pathway that has been linked to human diseases including myopathy, epilepsy, immunodeficiency, and cancer. Despite of the recent rapid progress of dissecting molecular mechanisms underlying SOCE activation, the development of therapies against dysfunctional SOCE significantly lags behind, partly due to the lack of more specific pharmacological tools and poor understanding of currently available SOCE modifiers, including the a newly identified SOCE inhibitor, digitoxin.
Objective and methods: Capitalizing on Ca2+ imaging and pharmacological tools, we aimed to systemically delineate the mechanism of action of digitoxin by defining how it impinges on Orai1 to exert its suppressive effect on SOCE.
Results: The SOCE-suppressive function of digitoxin is dependent on S27-S30 residues of wild-type Orai1. With 8h-incubation of digitoxin with STIM1-prebound Orai1 or a constitutively active mutant Orai1-ANSGA, its inhibition was no longer dependent on S27-S30 residues. Instead, the inhibition may involve the pore region of Orai1 channels, as V102C mutant at the pore region would greatly diminish or abolish the inhibition on pre-activated Orai1.
Conclusions: Our study identified two regions that are critical for the inhibition on Orai1 channels, providing valuable hotspots for future design of SOCE inhibitors.
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Cite this article as:
Digitoxin Suppresses Store Operated Calcium Entry by Modulating Phosphorylation and the Pore Region of Orai1, Current Molecular Medicine 2018; 18 (6) . https://dx.doi.org/10.2174/1566524018666181113111316
DOI https://dx.doi.org/10.2174/1566524018666181113111316 |
Print ISSN 1566-5240 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5666 |
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