β-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity
β-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity
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DOI：
10.1074/jbc.m700641200
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Kaczmarek, Leszek
中科院分区：
文献类型：
--
作者：
Michaluk, Piotr;Kolodziej, Lukasz;Kaczmarek, Leszek
基质金属蛋白酶-9是近年来在突触可塑性中控制细胞外蛋白分解的重要分子。然而，之前还没有发现其酶活性的突触靶点。在这份报告中，我们证明了β-营养不良蛋白聚糖包含了这样一个神经活性驱动的基质金属蛋白酶-9靶标。这一概念是基于以下观察所得。(I)重组的、自激活的基质金属蛋白酶-9产生有限的蛋白水解性切割β-肌营养不良多糖。(Ii)在神经元培养中，β-营养不良糖蛋白分解反应于谷氨酸或荷包牡丹碱刺激，并被金属蛋白酶组织抑制因子-1所阻断。(Iii)癫痫发作后，在体内的海马区也观察到了β-营养不良多糖的降解，但在基质金属蛋白酶9基因敲除的小鼠中没有观察到。(4)β-肌营养不良蛋白聚糖的裂解与基质金属蛋白酶-9活性的增加在时间上相关。(V)最后，β-肌营养不良聚糖和基质金属蛋白酶-9共存于海马区突触后元件中。综上所述，我们的数据证实，β-营养不良多糖是第一种基质金属蛋白酶-9底物，在突触活性增强时被消化。这一证明可能有助于理解这两种蛋白在神经元功能中的可能作用，特别是在突触可塑性、学习和记忆方面。
Matrix metalloproteinase-9 has recently emerged as an important molecule in control of extracellular proteolysis in the synaptic plasticity. However, no synaptic targets for its enzymatic activity had been identified before. In this report, we show that beta-dystroglycan comprises such a neuronal activity-driven target for matrix metalloproteinase-9. This notion is based on the following observations. (i) Recombinant, autoactivating matrix metalloproteinase-9 produces limited proteolytic cleavage of beta-dystroglycan. (ii) In neuronal cultures, beta-dystroglycan proteolysis occurs in response to stimulation with either glutamate or bicuculline and is blocked by tissue inhibitor of metalloproteinases-1, a metalloproteinase inhibitor. (iii) beta-Dystroglycan degradation is also observed in the hippocampus in vivo in response to seizures but not in the matrix metalloproteinase 9 knock-out mice. (iv) beta-Dystroglycan cleavage correlates in time with increased matrix metalloproteinase-9 activity. (v) Finally, beta-dystroglycan and matrix metalloproteinase-9 colocalize in postsynaptic elements in the hippocampus. In conclusion, our data identify the beta-dystroglycan as a first matrix metalloproteinase-9 substrate digested in response to enhanced synaptic activity. This demonstration may help to understand the possible role of both proteins in neuronal functions, especially in synaptic plasticity, learning, and memory.