Fang M, Jaffrey S R, Sawa A, Ye K, Luo X, Snyder S H
Department of Neuroscience, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21205, USA.
Neuron. 2000 Oct;28(1):183-93. doi: 10.1016/s0896-6273(00)00095-7.
Because nitric oxide (NO) is a highly reactive signaling molecule, chemical inactivation by reaction with oxygen, superoxide, and glutathione competes with specific interactions with target proteins. NO signaling may be enhanced by adaptor proteins that couple neuronal NO synthase (nNOS) to specific target proteins. Here we identify a selective interaction of the nNOS adaptor protein CAPON with Dexras1, a brain-enriched member of the Ras family of small monomeric G proteins. We find that Dexras1 is activated by NO donors as well as by NMDA receptor-stimulated NO synthesis in cortical neurons. The importance of Dexras1 as a physiologic target of nNOS is established by the selective decrease of Dexras1 activation, but not H-Ras or four other Ras family members, in the brains of mice harboring a targeted genomic deletion of nNOS (nNOS-/-). We also find that nNOS, CAPON, and Dexras1 form a ternary complex that enhances the ability of nNOS to activate Dexras1. These findings identify Dexras1 as a novel physiologic NO effector and suggest that anchoring of nNOS to specific targets is a mechanism by which NO signaling is enhanced.
由于一氧化氮（NO）是一种高反应性信号分子，其与氧气、超氧化物和谷胱甘肽发生反应导致的化学失活会与它和靶蛋白的特异性相互作用相互竞争。神经元型一氧化氮合酶（nNOS）与特定靶蛋白偶联的衔接蛋白可能会增强NO信号传导。在此，我们确定了nNOS衔接蛋白CAPON与Dexras1之间的选择性相互作用，Dexras1是小单体G蛋白Ras家族中一个在脑中富集的成员。我们发现，在皮质神经元中，Dexras1可被NO供体以及NMDA受体刺激的NO合成激活。在携带nNOS基因靶向缺失（nNOS-/-）的小鼠大脑中，Dexras1的激活选择性降低，而H-Ras或其他四个Ras家族成员的激活未受影响，这证实了Dexras1作为nNOS生理靶标的重要性。我们还发现，nNOS、CAPON和Dexras1形成三元复合物，增强了nNOS激活Dexras1的能力。这些发现确定Dexras1为一种新型的生理性NO效应器，并表明将nNOS锚定到特定靶标是增强NO信号传导的一种机制。
