STIM1对的寡合化ER耗尽到CRAC通道激活
Riina M Luik1, Bin Wang, Murali Prakriya
1Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature
|July 4, 2008
概括
流体相互作用分子1 (STIM1) 寡合化是激活释放激活 (CRAC) 通道的关键事件. 这一过程是由内质网膜中耗尽引发的,驱动储存运行的进入T细胞.
科学领域:
- 细胞生物学 细胞生物学
- 免疫学 免疫学 免疫学
- 生物化学 生物化学
背景情况:
- 释放激活通道 (CRAC) 对于T淋巴细胞的激活和增殖至关重要.
- 细胞内膜网膜 (ER) 耗尽启动肌体相互作用分子1 (STIM1) 的寡合化和重新分配到ER-血膜 (ER-PM) 结点,导致通过ORAI1.1.激活CRAC通道.
- 连接ER损失与这些分子重组的确切机制尚不清楚.
研究的目的:
- 阐明ER水平,STIM1再分配和CRAC通道激活之间的关系.
- 为了确定STIM1寡合化作为关键的依赖事件驱动商店运行的入口.
主要方法:
- 利用具有ER向指标的人类Jurkat白血病T细胞来监测CRAC通道激活和STIM1再分配.
- 量化了细胞内水平与STIM1再分配/CRAC通道激活之间的关系.
- 通过将其感应域替换为FKBP12或FRB域来改造STIM1变种.
- 诱导的STIM1融合蛋白质寡合化,使用拉帕胺类同类物来评估其在CRAC通道激活中的作用.
主要成果:
- CRAC通道激活和STIM1再分配对ER水平具有相似的依赖性,半最大激活约为200μM,Hill系数约为4.
- 尽管STIM1只结合一种离子,但显而易见的高合作性表明,对于ER-PM结积,STIM1寡合化是必要的.
- 在ER-PM连接处的STIM1融合蛋白的诱导性寡合化,独立于ER耗尽,激活了CRAC通道.
- 证实STIM1寡合化是关键事件,将ER储量耗尽与储量运行的入量联系起来.
结论:
- STIM1寡合化作为一个关键开关,转导ER储量耗尽的信号,以启动储存运行的进入.
- 这种寡合化事件驱动了在ER-PM连接处的STIM1-ORAI1集群的自我组织和激活,这对于细胞信号传输至关重要.
相关概念视频
GPCR Desensitization
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...
G-Protein Gated Ion Channels
GPCRs are primarily responsible for our sense of smell, taste, and vision. The binding of a sensory stimulus activates GPCR to stimulate effector proteins, many of which are ion channels in the sensory organs. GPCRs modulate the opening and closing of the target ion channels either directly by binding them, or by releasing second messengers that activate these channels. As ions move across the membrane, the membrane potential is altered, which induces an appropriate response.
Sensory organs,...
Sensory organs,...
GPCRs Regulate Adenylyl Cylase Activity
Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Two...
Feedback Regulation of Calcium Concentration
Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Calmodulin-dependent Signaling
Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...
Ligand-Gated Ion Channel Receptor: Gating Mechanism
Ligand-gated ion channels are transmembrane proteins that play a vital role in intercellular communication and functions of the nervous system. They allow the influx of ions across the membrane once the neurotransmitter binds, allowing the subsequent transmission of electrical excitation across the neurons. Other ligand-gated ion channels, like the γ-aminobutyric acid (GABA) receptor, permit anions like chloride into the cells on the binding of the GABA molecule. Their entry into the cell...


