LRRC8A通过增强NMDA受体活性和激活线粒体亡途径来调解缺血性神经损伤
Chengli Qian1,2, Linshu Huang1, Ying Chen1
1Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China.
Cell biology international
|December 22, 2025
概括
大脑缺血可调节高氨酸丰富的重复含有蛋白8A (LRRC8A),促进神经元亡和中风损伤. 抑制LRRC8A通过调节NMDA受体活性来减少脑损伤和亡.
科学领域:
- 神经科学是一个神经科学.
- 分子生物学分子生物学
- 病理学 病理学 病理学
背景情况:
- 脑缺血是中风的主要原因,引发神经元亡,大大导致脑损伤.
- 驱动缺血引起的神经元亡的精确分子机制尚未完全阐明.
- 体积调节的离子通道,特别是含有丰富白的重复含有蛋白8A (LRRC8A) 亚单元,都与细胞应激反应有关.
研究的目的:
- 研究LRRC8A在脑缺血后的神经细胞亡中的作用.
- 阐明LRRC8A有助于缺血引起的神经元损伤的分子机制.
- 评估LRRC8A作为缺血性中风的潜在治疗点.
主要方法:
- 利用中脑动脉阻塞 (MCAO) 的老鼠模型来模拟缺血性中风条件.
- 在培养的神经元中使用氧气-葡萄糖剥夺 (OGD) 来模仿体外缺血/缺氧.
- 研究了LRRC8A表达和功能,使用小干扰RNA (siRNA) 进行基因淘汰.
- 分析了线粒体亡途径 (Bax/Bcl-2/Caspase-9/Caspase-3) 和NMDA受体 (NMDAR) 的活性.
主要成果:
- 大脑缺血症 (MCAO和OGD) 迅速增加了apoptotic神经元中的LRRC8A表达.
- 在MCAO大鼠中,通过siRNA的LRRC8A敲击显著降低了脑梗塞的大小和改善了神经功能.
- 通过siRNA介导的LRRC8A的淘汰抑制了线粒体亡途径的激活,并降低了神经元亡.
- LRRC8A的淘汰扭转了OGD诱导的NMDARs过度激活,并削弱了LRRC8A和NMDAR子单元GluN1.1之间的相互作用.
结论:
- 神经元LRRC8A表达在脑缺血期间被上调,并导致神经元亡.
- LRRC8A促进NMDAR过活,可能通过与GluN1的相互作用,导致线粒体介导的亡.
- 向LRRC8A是一个有希望的治疗策略,用于减少缺血性中风中神经元损伤.
相关概念视频
01:17The Extrinsic Apoptotic Pathway
8.0K
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
8.0K
01:31The Intrinsic Apoptotic Pathway
8.2K
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
8.2K
01:16Necrosis
6.2K
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
6.2K
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
3.7K
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...
3.7K