CAPON-nNOS coupling can serve as a target for developing new anxiolytics
CAPON-nNOS coupling can serve as a target for developing new anxiolytics
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CAPON-nNOS 耦合可以作为开发新型抗焦虑药的目标
DOI：
10.1038/nm.3644
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发表时间：
2014-08
期刊：
影响因子：
82.9
通讯作者：
Zhu, Dong-Ya
中科院分区：
文献类型：
--
作者：
Hu, Xiao-Ling;Zhang, Jing;Wu, Hai-Yin;Zhu, Dong-Ya
焦虑症是一种非常普遍的精神疾病。需要更深入地了解哺乳动物大脑中的焦虑控制机制，并开发新的抗焦虑药物。本文报道神经元型一氧化氮合酶(NNOS)与其羧基末端的PDZ配体(Capon)之间的偶联作用，可作为开发新的抗焦虑药物的靶点。通过过表达全长Capon来加强nNOS-Capon在小鼠海马区的相互作用可以产生焦虑样行为，而通过在小鼠海马区过表达Capon-125C或Capon-20C(Capon的C端125或20个氨基酸)或在小鼠海马区传递Tat-Capon-12C(包含TAT和Capon的12个C端氨基酸的肽)使Capon从nNOS解离出来，可以产生抗焦虑的作用。慢性轻度应激(CMS)的小鼠表现出海马区nNOS-Capon偶联的显著增加，并随之而来的是类似焦虑的表型。阻断nNOS-Capon偶联可逆转CMS诱导的类焦虑行为。此外，nNOS-Capon结合的小分子阻断剂很快就会产生类似焦虑的效果。地塞米松诱导的ras蛋白1(Dexras1)-细胞外信号调节激酶(ERK)信号转导参与了nNOS-Capon关联的行为效应。因此，nNOS-Capon关联通过调节Dexras1-ERK信号参与焦虑相关行为的调节，并可作为开发潜在抗焦虑药物的靶点。
Anxiety disorders are highly prevalent psychiatric diseases,. There is need for a deeper understanding of anxiety control mechanisms in the mammalian brain and for development of new anxiolytic agents. Here we report that the coupling between neuronal nitric oxide synthase (nNOS) and its carboxy-terminal PDZ ligand (CAPON) can serve as a target for developing new anxiolytic agents. Augmenting nNOS-CAPON interaction in the hippocampus of mice by overexpressing full-length CAPON gave rise to anxiogenic-like behaviors, whereas dissociating CAPON from nNOS by overexpressing CAPON-125C or CAPON-20C (the C-terminal 125 or 20 amino acids of CAPON) or delivering Tat-CAPON-12C (a peptide comprising Tat and the 12 C-terminal amino acids of CAPON) in the hippocampus of mice produced anxiolytic-like effects. Mice subjected to chronic mild stress (CMS) displayed a substantial increase in nNOS-CAPON coupling in the hippocampus and a consequent anxiogenic-like phenotype. Disrupting nNOS-CAPON coupling reversed the CMS-induced anxiogenic-like behaviors. Moreover, small-molecule blockers of nNOS-CAPON binding rapidly produced anxiolytic-like effects. Dexamethasone-induced ras protein 1 (Dexras1)–extracellular signal–regulated kinase (ERK) signaling was involved in the behavioral effects of nNOS-CAPON association. Thus, nNOS-CAPON association contributes to the modulation of anxiety-related behaviors via regulating Dexras1-ERK signaling and can serve as a target for developing potential anxiolytics.
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影响因子：
64.8
作者：
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