title: CAPON-nNOS coupling can serve as a target for developing new anxiolytics.
abstract: 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.
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China. [3].
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: 1] Department of Medicinal Chemistry, Nanjing Medical University, Nanjing, China. [2].
authors.forename: Ting-You
authors.initials: TY
authors.lastname: Li
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, Nanjing Medical University, Nanjing, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Medicinal Chemistry, Nanjing Medical University, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chang
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Lin
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Zhou
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 1] Department of Neurobiology, Nanjing Medical University, Nanjing, China. [2].
authors.forename: Wei
authors.initials: W
authors.lastname: Lu
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Gao
authors.affiliation: Department of Medicinal Chemistry, Nanjing Medical University, Nanjing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Qi-Gang
authors.initials: QG
authors.lastname: Zhou
authors.affiliation: Department of Chemistry, Nanjing Medical University, Nanjing, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Center of Drug Metabolism &Pharmacokinetics, Jiangsu Simcere Pharmaceutical, Nanjing, China.
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Hai-Yin
authors.initials: HY
authors.lastname: Wu
authors.affiliation: 1] Laboratory of Cerebrovascular Disease, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China. [2] Department of Pharmacology, Nanjing Medical University, Nanjing, China.
authors.forename: Dong-Ya
authors.initials: DY
authors.lastname: Zhu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D006801:Humans; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014151:Anti-Anxiety Agents; C488081:NOS1AP protein, human; D052248:Nitric Oxide Synthase Type I