Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release.
Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release.
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DOI：
10.1016/j.isci.2023.106669
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发表时间：
2023-05-19
期刊：
影响因子：
5.8
通讯作者：
Mongin, Alexander A.
中科院分区：
文献类型：
--
作者：
Balkaya, Mustafa;Dohare, Preeti;Chen, Sophie;Schobler, Alexandra L.;Fidaleo, Antonio M.;Nalwalk, Julia W.;Sah, Rajan;Mongin, Alexander A.
普遍存在的体积调节阴离子通道（VRAC）有助于细胞体积控制并有助于许多其他生理过程。使用非特异性 VRAC 阻滞剂或大脑特异性删除必需的 VRAC 亚基 LRRC8A 进行治疗对啮齿动物中风模型具有高度保护作用。在这里，我们测试了广泛接受的观点，即 VRAC 的有害影响是由兴奋性神经递质谷氨酸的释放介导的。我们仅在星形胶质细胞或大多数脑细胞中进行了条件性 LRRC8A 敲除。转基因小鼠遭受实验性中风（大脑中动脉闭塞）。星形细胞 LRRC8A 敲除没有产生保护作用。相反，全脑 LRRC8A 缺失显着减少了杂合子 (Het) 和完全 KO 小鼠的脑梗塞。然而，尽管有相同的保护作用，Het 小鼠仍具有完全肿胀激活的谷氨酸释放，而 KO 小鼠则几乎没有这种情况。这些发现表明 LRRC8A 通过 VRAC 介导的谷氨酸释放以外的机制导致缺血性脑损伤。通过 VRAC 通道的谷氨酸释放被认为会导致中风中的脑损伤 VRAC 蛋白 LRRC8A 的完全和杂合性缺失同样会减少中风损伤 LRRC8A KO 小鼠中通过 VRAC 释放的肿胀激活的谷氨酸会丢失，但 Het 小鼠不会丢失 VRAC 参与中风损伤背后的机制必须重新审视分子生物学；分子神经科学；细胞生物学
The ubiquitous volume-regulated anion channels (VRACs) facilitate cell volume control and contribute to many other physiological processes. Treatment with non-specific VRAC blockers or brain-specific deletion of the essential VRAC subunit LRRC8A is highly protective in rodent models of stroke. Here, we tested the widely accepted idea that the harmful effects of VRACs are mediated by release of the excitatory neurotransmitter glutamate. We produced conditional LRRC8A knockout either exclusively in astrocytes or in the majority of brain cells. Genetically modified mice were subjected to an experimental stroke (middle cerebral artery occlusion). The astrocytic LRRC8A knockout yielded no protection. Conversely, the brain-wide LRRC8A deletion strongly reduced cerebral infarction in both heterozygous (Het) and full KO mice. Yet, despite identical protection, Het mice had full swelling-activated glutamate release, whereas KO animals showed its virtual absence. These findings suggest that LRRC8A contributes to ischemic brain injury via a mechanism other than VRAC-mediated glutamate release. Glutamate release via VRAC channels is thought to drive brain injury in stroke Full and heterozygous loss of the VRAC protein LRRC8A equally reduces stroke damage Swelling-activated glutamate release via VRAC is lost in LRRC8A KO but not Het mice The mechanism behind VRAC involvement in stroke injury must be revisited Molecular biology; Molecular neuroscience; Cell biology
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DOI：
10.1152/ajpheart.00686.2002
发表时间：
2003-08-01
影响因子：
4.8
作者：
He, JY;Kargacin, ME;Ward, CA
通讯作者：
Ward, CA
影响因子：
7.7
作者：
Alghanem AF;Abello J;Maurer JM;Kumar A;Ta CM;Gunasekar SK;Fatima U;Kang C;Xie L;Adeola O;Riker M;Elliot-Hudson M;Minerath RA;Grueter CE;Mullins RF;Stratman AN;Sah R
通讯作者：
Sah R
影响因子：
5
作者：
Feng, YZ;Fratkins, JD;LeBlanc, MH
通讯作者：
LeBlanc, MH
影响因子：
8.3
作者：
Alkayed, NJ;Birks, EK;Harder, DR
通讯作者：
Harder, DR
影响因子：
4.1
作者：
Boulos, Alan S.;Deshaies, Eric M.;Drazin, Doniel
通讯作者：
Drazin, Doniel