Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity.
Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity.
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DOI：
10.1111/jnc.12293
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发表时间：
2013-10
影响因子：
4.7
通讯作者：
Scarisbrick IA
中科院分区：
文献类型：
--
作者：
Yoon H;Radulovic M;Wu J;Blaber SI;Blaber M;Fehlings MG;Scarisbrick IA
CNS创伤产生蛋白水解失衡，导致继发性损伤，包括轴突病和神经元变性。激肽释放酶6（Klk 6）是一种丝氨酸蛋白酶，参与神经变性，在这里，我们研究蛋白酶激活受体1（PAR 1）和PAR 2在介导这些影响的作用。首先，我们证明Klk 6和PAR 1的原型激活剂凝血酶以及PAR 1和PAR 2在小鼠实验性创伤性脊髓损伤（SCI）中在急性或亚急性时间点均升高。重组Klk 6以PI 3 K和MEK依赖的方式触发小脑颗粒神经元和NSC 34脊髓运动神经元细胞系中的ERK 1/2信号传导。重要的是，PAR 1或PAR 2的脂肽抑制剂和PAR 1基因缺失各自降低Klk 6-ERK 1/2活化。此外，Klk 6和凝血酶促进小脑神经元的变性并加重谷氨酸神经毒性。此外，PAR 1的基因缺失阻断凝血酶介导的小脑神经毒性，并降低Klk 6的神经毒性作用。Klk 6还增加了NSC 34运动神经元中谷氨酸介导的Bim信号传导、PARP裂解和乳酸脱氢酶（LDH）释放，并且这些作用被PAR 1和PAR 2脂肽抑制剂阻断。总之，这些数据指出了CNS神经元中由PAR 1和PAR 2介导的新Klk 6信号传导轴，其被定位为有助于神经变性。
CNS trauma generates a proteolytic imbalance contributing to secondary injury, including axonopathy and neuron degeneration. Kallikrein 6 (Klk6) is a serine protease implicated in neurodegeneration and here we investigate the role of protease activated receptors 1 (PAR1) and PAR2 in mediating these effects. First we demonstrate Klk6 and the prototypical activator of PAR1, thrombin, as well as PAR1 and PAR2, are each elevated in murine experimental traumatic spinal cord injury (SCI) at acute or subacute time points. Recombinant Klk6 triggered ERK1/2 signaling in cerebellar granule neurons and in the NSC34 spinal cord motoneuron cell line, in a PI3K and MEK-dependent fashion. Importantly, lipopeptide inhibitors of PAR1 or PAR2, and PAR1 genetic deletion, each reduced Klk6-ERK1/2 activation. In addition, Klk6 and thrombin promoted degeneration of cerebellar neurons and exacerbated glutamate neurotoxicity. Moreover, genetic deletion of PAR1 blocked thrombin-mediated cerebellar neurotoxicity and reduced the neurotoxic effects of Klk6. Klk6 also increased glutamate-mediated Bim signaling, PARP cleavage and lactate dehydrogenase (LDH) release in NSC34 motoneurons and these effects were blocked by PAR1 and PAR2 lipopeptide inhibitors. Taken together these data point to a novel Klk6-signaling axis in CNS neurons that is mediated by PAR1 and PAR2 and is positioned to contribute to neurodegeneration.
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影响因子：
2.9
作者：
Blaber, SI;Scarisbrick, IA;Blaber, M
通讯作者：
Blaber, M
影响因子：
5.3
作者：
Biasini，Emiliano;Unterberger，Ursula;Harris，David A.
通讯作者：
Harris，David A.
DOI：
10.1097/01.jnen.0000196133.74087.cb
发表时间：
2006-01-01
影响因子：
3.2
作者：
Arai, T;Miklossy, J;McGeer, PL
通讯作者：
McGeer, PL
影响因子：
4.7
作者：
Christophi, GP;Jackson, PJ;Scarisbrick, IA
通讯作者：
Scarisbrick, IA
影响因子：
5.3
作者：
Choi, SH;Lee, DY;Jin, BK
通讯作者：
Jin, BK