Identification of a molecular target for glutamate regulation of astrocyte water permeability
Identification of a molecular target for glutamate regulation of astrocyte water permeability
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DOI：
10.1002/glia.20627
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发表时间：
2008-04-15
期刊：
影响因子：
6.2
通讯作者：
Aperia, Anita
中科院分区：
文献类型：
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作者：
Gunnarson, Eli;Zelenina, Marina;Aperia, Anita
星形胶质细胞在维持脑水稳态方面发挥着关键作用，但对于星形胶质细胞水渗透性的短期调节机制知之甚少。在这里，我们报道谷氨酸增加星形胶质细胞的水渗透性，并且这种作用的分子靶标是水通道蛋白4（AQP4）丝氨酸111残基，它处于控制水通道门控的战略位置。谷氨酸效应涉及 I 类代谢型谷氨酸受体 (mGluR) 的激活、细胞内钙的释放以及钙/钙调蛋白依赖性蛋白激酶 II (CaMKII) 和一氧化氮合酶 (NOS) 的激活。我们发现 mGluR 激活会增加急性大鼠海马切片中低渗组织肿胀的速度，这一发现强调了我们结果的生理影响。脑缺血与谷氨酸的过度释放有关，在缺血后脑水肿中消除 AQP4 可减轻损伤程度。因此，我们已将 AQP4 确定为可以减轻脑水肿发展的药物的分子靶标。 (C) 2008 Wiley-Liss, Inc.
Astrocytes play a key role for maintenance of brain water homeostasis, but little is known about mechanisms of short-term regulation of astrocyte water permeability. Here, we report that glutamate increases astrocyte water permeability and that the molecular target for this effect is the aquaporin-4 (AQP4) serine 111 residue, which is in a strategic position for control of the water channel gating. The glutamate effect involves activation of group I metabotropic glutamate receptors (mGluR), intracellular calcium release, and activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and nitric oxide synthase (NOS). The physiological impact of our results is underlined by the finding that mGluR activation increases the rate of hypoosmotic tissue swelling in acute rat hippocampal slices. Cerebral ischemia is associated with an excessive release of glutamate, and in postischemic cerebral edema ablation of AQP4 attenuates the degree of damage. Thus, we have identified AQP4 as the molecular target for drugs that may attenuate the development of brain edema. (C) 2008 Wiley-Liss, Inc.