Cheah Jaime H, Kim Sangwon F, Hester Lynda D, Clancy Kathleen W, Patterson Stanley E, Papadopoulos Vassilios, Snyder Solomon H
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Neuron. 2006 Aug 17;51(4):431-40. doi: 10.1016/j.neuron.2006.07.011.
Dexras1 is a 30 kDa G protein in the Ras subfamily whose discovery was based on its pronounced inducibility by the glucocorticoid dexamethasone. It binds to neuronal nitric oxide synthase (nNOS) via the adaptor protein CAPON, eliciting S-nitrosylation and activation of Dexras1. We report that Dexras1 binds to the peripheral benzodiazepine receptor-associated protein (PAP7), a protein of unknown function that binds to cyclic AMP-dependent protein kinase and the peripheral benzodiazepine receptor. PAP7 in turn binds to the divalent metal transporter (DMT1), an iron import channel. We have identified a signaling cascade in neurons whereby stimulation of NMDA receptors activates nNOS, leading to S-nitrosylation and activation of Dexras1, which, via PAP7 and DMT1, physiologically induces iron uptake. As selective iron chelation prevents NMDA neurotoxicity in cortical cultures, the NMDA-NO-Dexras1-PAP7-DMT1-iron uptake signaling cascade also appears to mediate NMDA neurotoxicity.
Dexras1是Ras亚家族中的一种30 kDa G蛋白，其发现基于它受糖皮质激素地塞米松的显著诱导作用。它通过衔接蛋白CAPON与神经元型一氧化氮合酶（nNOS）结合，引发Dexras1的S-亚硝基化和激活。我们报告Dexras1与外周苯二氮䓬受体相关蛋白（PAP7）结合，PAP7是一种功能未知的蛋白，它与环磷酸腺苷依赖性蛋白激酶和外周苯二氮䓬受体结合。PAP7继而与二价金属转运体（DMT1）结合，DMT1是一种铁导入通道。我们在神经元中鉴定出一种信号级联反应，即N-甲基-D-天冬氨酸（NMDA）受体的刺激激活nNOS，导致Dexras1的S-亚硝基化和激活，Dexras1通过PAP7和DMT1在生理上诱导铁摄取。由于选择性铁螯合可防止皮质培养物中的NMDA神经毒性，NMDA-NO-Dexras1-PAP7-DMT1-铁摄取信号级联反应似乎也介导了NMDA神经毒性。
