Molecular mechanism of effect of secreted active neuropsin on neighboring synapses

蛋白酶介导的信号是神经系统的重要调节剂。然而，鉴定这些蛋白酶的特定信号底物受到中间底物形式被切割和释放的速度的限制。本研究开发了一种检测非裂解酶结合形式的筛选方法，并用于鉴定一种新的神经蛋白/神经调节蛋白-1（NRG-1）蛋白水解信号系统，该系统特异性定位于突触间隙的微域。胞外蛋白酶neuropsin在三个新发现的位点上切割成熟的NRG-1（包括NRG-1胞外结构域），以去除NRG-1肝素结合结构域。这从基质-糖胺聚糖池中释放了配体部分，使其能够磷酸化NRG-1受体p185（ErbB4）。因此，加工过的nrg -1- erbb4信号有助于调节Schaffer侧枝的早期长期增强。该信号系统可能对动物和人类的认知都很重要，其功能障碍可能导致人类精神障碍，如精神分裂症和双相情感障碍。

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 non-cleaved enzyme-bound forms was developed and used to identify a novel neuropsin/neuregulin-1(NRG-1) proteolytic signaling system, which is specifically localized in microdomain of synaptic cleft. The extracellular protease, neuropsin, cleaved mature NRG-1(comprising the NRG-1 extracellular domain) at three newly-identified sites to remove the NRG-1 heparin-binding domain. This released the ligand moiety from the matrix-glycosaminoglycan pool and enabled it to phosphorylate the NRG-1 receptor, p185(ErbB4). Thus, processed-NRG-1-ErbB4 signaling contributes to the modulation of early-phase long-term potentiation of Schaffer collaterals. This signaling system may be important for both animal and human cognition, and its dysfunction may contribute to human mental disorders such as schizophrenia and bipolar disorder.