Molecular mechanism of effect of secreted active neuropsin on neighboring synapses

蛋白水解酶介导的信号转导是神经系统的重要调节器。然而，识别这类酶的特定信号底物受到中间底物被切割和释放的速度的限制。在这里，我们建立了一种检测非裂解酶结合形式的筛选方法，并用于鉴定一个新的神经蛋白/神经调节蛋白-1(NRG-1)蛋白分解信号系统，该信号系统特异性地定位于突触裂隙的微域。细胞外蛋白水解酶，神经蛋白酶，在三个新发现的位置上裂解成熟的NRG-1(包括NRG-1的胞外区)，以去除NRG-1的肝素结合域。这释放了基质-糖胺聚糖池中的配体部分，并使其能够磷酸化NRG-1受体p185(ErbB4)。因此，Proceded-NRG-1-ErbB4信号有助于调节Schaffer侧支的早期长时程增强。这个信号系统可能对动物和人类的认知都很重要，它的功能障碍可能会导致精神分裂症和双相情感障碍等人类精神障碍。

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.