Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.
Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke.
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DOI：
10.1126/scisignal.add6364
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发表时间：
2023-06-06
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
脑肿胀导致各种脑损伤和疾病的发病率和死亡率，但缺乏有效的治疗方法。脑肿胀与水通过水通道蛋白流入血管周围的星形胶质细胞有关。星形胶质细胞中的水积聚增加了它们的体积，这有助于脑肿胀。使用严重缺血性中风的小鼠模型，我们确定了一个潜在的靶向机制，促进水通道蛋白4（AQP 4）在血管周围星形胶质细胞终足的细胞表面定位，完全包住大脑的毛细血管。脑缺血增加了异聚阳离子通道SUR 1-TRPM 4和血管周围星形胶质细胞终足中Na+/Ca 2+交换器NCX 1的丰度。Na+通过SUR 1-TRPM 4的内流诱导Ca 2+通过NCX 1以反向模式运转进入细胞，从而提高了Ca 2+的端足内浓度。这种Ca 2+的增加刺激了AQP 4向质膜的钙调素依赖性易位和水内流，从而导致细胞水肿和脑肿胀。药理学抑制或星形胶质细胞特异性缺失SUR 1-TRPM 4或NCX 1可降低小鼠脑肿胀并改善神经功能，其程度与AQP 4抑制剂相似，且与梗死面积无关。因此，星形胶质细胞终足中的通道可以被靶向以减少中风患者的缺血后脑肿胀。
Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain’s capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na+/Ca2+ exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na+ through SUR1-TRPM4 induced Ca2+ transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca2+. This increase in Ca2+ stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce post-ischemic brain swelling in stroke patients.
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影响因子：
16.2
作者：
Cho C;Smallwood PM;Nathans J
通讯作者：
Nathans J
影响因子：
5.6
作者：
Gleiser C;Wagner A;Fallier-Becker P;Wolburg H;Hirt B;Mack AF
通讯作者：
Mack AF
DOI：
10.1007/s11936-013-0275-0
发表时间：
2014-01-01
影响因子：
--
作者：
Arch, Allison E;Sheth, Kevin N
通讯作者：
Sheth, Kevin N
影响因子：
1.2
作者：
Frank, Dmitry;Gruenbaum, Benjamin F.;Boyko, Matthew
通讯作者：
Boyko, Matthew
DOI：
10.3791/51240
发表时间：
2014-04-03
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Gabriel LR;Wu S;Melikian HE
通讯作者：
Melikian HE