Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes
Protease-activated receptor-1 in human brain: localization and functional expression in astrocytes
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DOI：
10.1016/j.expneurol.2004.02.018
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发表时间：
2004-07-01
影响因子：
5.3
通讯作者：
Traynelis, SF
中科院分区：
文献类型：
--
作者：
Junge, CE;Lee, CJ;Traynelis, SF
蛋白酶激活受体-1（PAR 1）是一种G蛋白偶联受体，由血液来源的丝氨酸蛋白酶蛋白水解激活。尽管PARI以其在凝血和止血中的作用而闻名，但最近的研究结果表明，PAR 1激活除了在血管系统中的作用外，还在中枢神经系统（CNS）中起作用。啮齿类动物的研究表明，PAR 1在整个大脑的神经元和星形胶质细胞上表达。在中风和脑损伤的动物模型中，体外和体内PAR 1活化似乎影响神经变性和神经保护。由于越来越多的证据表明PAR 1在中枢神经系统中具有重要而多样的作用，我们对PAR 1在人脑中的蛋白定位和功能进行了研究。PAR 1在白色和灰质的星形胶质细胞中表达最强，在神经元中适度表达。PAR 1和GFAP共定位表明PAR 1在细胞体和包埋毛细血管的星形胶质细胞终足上表达。PAR 1在U178 MG人胶质母细胞瘤细胞系中的激活增加了P1水解和细胞内Ca 2+，表明PAR 1在人胶质源性肿瘤细胞中是功能性的。人星形胶质细胞和人胶质母细胞瘤细胞的原代培养物通过增加细胞内Ca 2+对PAR 1活化作出响应。总之，这些结果表明，PAR 1在人脑中表达，并在神经胶质肿瘤和培养物中发挥作用。由于丝氨酸蛋白酶可以进入脑组织，并激活PAR 1时，血脑屏障（BBB）打破，药理学操纵PAR 1信号可能提供一个潜在的治疗目标，在人类神经系统疾病的神经保护。(C)2004年爱思唯尔公司All rights reserved.
Protease-activated receptor-1 (PAR1) is a G-protein coupled receptor that is proteolytically activated by blood-derived serine proteases. Although PARI is best known for its role in coagulation and hemostasis, recent findings demonstrate that PAR1 activation has actions in the central nervous system (CNS) apart from its role in the vasculature. Rodent studies have demonstrated that PAR1 is expressed throughout the brain on neurons and astrocytes. PAR1 activation in vitro and in vivo appears to influence neurodegeneration and neuroprotection in animal models of stroke and brain injury. Because of increasing evidence that PAR1 has important and diverse roles in the CNS, we explored the protein localization and function of PAR1 in human brain. PAR1 is most intensely expressed in astrocytes of white and gray matter and moderately expressed in neurons. PAR1 and GFAP co-localization demonstrates that PAR1 is expressed on the cell body and on astrocytic endfeet that invest capillaries. PAR1 activation in the U178MG human glioblastoma cell line increased P1 hydrolysis and intracellular Ca2+, indicating that PAR1 is functional in human glial-derived tumor cells. Primary cultures of human astrocytes and human glioblastoma cells respond to PAR1 activation by increasing intracellular Ca2+. Together, these results demonstrate that PAR1 is expressed in human brain and functional in glial tumors and cultures derived from it. Because serine proteases may enter brain tissue and activate PAR1 when the blood brain barrier (BBB) breaks down, pharmacological manipulation of PAR1 signaling may provide a potential therapeutic target for neuroprotection in human neurological disorders. (C) 2004 Elsevier Inc. All rights reserved.