Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons - Implications for the regulation of motor learning and neuronal survival
Neuroserpin, a brain-associated inhibitor of tissue plasminogen activator is localized primarily in neurons - Implications for the regulation of motor learning and neuronal survival
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DOI：
10.1074/jbc.272.52.33062
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发表时间：
1997-12-26
影响因子：
4.8
通讯作者：
Lawrence, DA
中科院分区：
文献类型：
--
作者：
Hastings, GA;Coleman, TA;Lawrence, DA
从人全脑基因文库中克隆了丝氨酸蛋白酶抑制物神经丝氨酸，并在昆虫细胞中表达了重组蛋白。纯化的蛋白是一种有效的组织型纤溶酶原激活物(TPA)的抑制物，对双链形式的表观二级速率常数为6.2×10(5)M-1 S(-1)。然而，与其他已知的纤溶酶原激活剂抑制物不同，神经丝氨酸是tPA的更有效的灭活剂，而不是尿激酶型纤溶酶原激活剂，神经丝氨酸也有效地抑制胰酶和神经生长因子-γ，但与纤溶酶和凝血酶的反应很慢，Northern印迹分析显示1.8kb碱基的信使RNA主要在成人脑和脊髓中表达，正常小鼠组织的免疫组织化学研究发现主要在神经细胞中有强染色，偶尔有小胶质细胞阳性。在脉络丛的室管膜细胞、小脑的浦肯野细胞、下丘脑和海马区的部分神经元以及在连合处的有髓轴突中，tPA的表达最明显，据报道，这些区域的tPA高表达，并且先前与运动学习和神经元存活有关，这些数据提示，神经丝氨酸可能是中枢神经系统tPA活性的关键调节因子，因此可能在神经元的可塑性和/或维持中发挥重要作用。
A cDNA clone for the serine proteinase inhibitor (serpin), neuroserpin, was isolated from a human whole brain cDNA library, and recombinant protein was expressed in insect cells, The purified protein is an efficient inhibitor of tissue type plasminogen activator (tPA), having an apparent second-order rate constant of 6.2 x 10(5) M-1 s(-1) for the two-chain form. However, unlike other known plasminogen activator inhibitors, neuroserpin is a more effective inactivator of tPA than of urokinase-type plasminogen activator, Neuroserpin also effectively inhibited trypsin and nerve growth factor-gamma but reacted only slowly with plasmin and thrombin, Northern blot analysis showed a 1.8 kilobase messenger RNA expressed predominantly in adult human brain and spinal cord, and immunohistochemical studies of normal mouse tissue detected strong staining primarily in neuronal cells with occasionally positive microglial cells. Staining was most prominent in the ependymal cells of the choroid plexus, Purkinje cells of the cerebellum, select neurons of the hypothalamus and hippocampus, and in the myelinated axons of the commissura, Expression of tPA within these regions is reported to be high and has previously been correlated with both motor learning and neuronal survival, Taken together, these data suggest that neuroserpin is likely to be a critical regulator of tPA activity in the central nervous system, and as such may play an important role in neuronal plasticity and/or maintenance.