Protease-mediated signaling is an important modulator of the nervous system. However, identifying the specific signaling substrates of such proteases is limited by the rapidity with which intermediate substrate forms are cleaved and released. Here, a screening method to detect noncleaved enzyme-bound forms was developed and used to identify a novel neuropsin/neuregulin-1 (NRG-1) proteolytic signaling system, which is specifically localized in the microdomain of synaptic cleft, in the mouse hippocampus. The extracellular protease, neuropsin, cleaved mature NRG-1 (comprising the extracellular domain of the NRG-1) at three newly identified sites to remove the heparin-binding domain of NRG-1. This released the ligand moiety from the matrix-glycosaminoglycan pool and enabled it to trigger the phosphorylation of NRG-1 receptor, p185 (ErbB4). Proteolysis of mature NRG-1 by neuropsin led to colocalization of the processed NRG-1 with ErbB4 in parvalbumin-positive hippocampal interneurons and consequent phosphorylation of tyrosine residues of proteins in the cells. Moreover, neuropsin knock-out mice exhibited impairments in Schaffer collateral early phase long-term potentiation, and application of the recombinant NRG-1 lacking heparin-binding activity reversed the effects through the activation of ErbB4 and GABA(A) receptors. Thus, ErbB4 signaling induced by neuropsin-dependent processing of NRG-1 contributes to the modulation of synaptic plasticity via regulation of GABAergic transmission. This signaling system may be involved in human cognition and mental disorders, such as schizophrenia and bipolar disorder, by its dysfunction.

译文

蛋白酶介导的信号传导是神经系统的重要调节剂。然而,鉴定这种蛋白酶的特定信号传导底物受到中间底物形式被裂解和释放的速度的限制。在这里,开发了一种检测未裂解酶结合形式的筛选方法,并将其用于鉴定新的神经蛋白酶/neuregulin-1 (NRG-1) 蛋白水解信号系统,该系统特别位于小鼠海马的突触间隙的微域中。细胞外蛋白酶神经蛋白酶在三个新鉴定的位点切割成熟NRG-1 (包括NRG-1的细胞外结构域) 以去除NRG-1的肝素结合结构域。这从基质-糖胺聚糖库释放配体部分,并使其能够触发NRG-1受体p185 (ErbB4) 的磷酸化。神经蛋白酶对成熟NRG-1的蛋白水解导致加工NRG-1与ErbB4在小白蛋白阳性海马中间神经元中的共定位,并导致细胞中蛋白质的酪氨酸残基磷酸化。此外,神经蛋白酶敲除小鼠在Schaffer附带的早期长期增强中表现出损伤,并且缺乏肝素结合活性的重组NRG-1的应用通过激活ErbB4和GABA(A) 受体逆转了作用。因此,由神经蛋白酶依赖性NRG-1处理诱导的ErbB4信号通过调节gaba能传递而有助于调节突触可塑性。该信号系统可能因其功能障碍而参与人类认知和精神障碍,例如精神分裂症和躁郁症。

+1
+2
100研值 100研值 ¥99课程
检索文献一次
下载文献一次

去下载>

成功解锁2个技能,为你点赞

《SCI写作十大必备语法》
解决你的SCI语法难题!

技能熟练度+1

视频课《玩转文献检索》
让你成为检索达人!

恭喜完成新手挑战

手机微信扫一扫,添加好友领取

免费领《Endnote文献管理工具+教程》

微信扫码, 免费领取

手机登录

获取验证码
登录