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.

NOS1AP Functionally Associates with YAP To Regulate Hippo Signaling

“…In summary, we have shown that NOS1AP is a highly spliced protein, with the different isoforms having differential tissue expression and subcellular localizations and forming different signaling complexes. Given that NOS1AP has been implicated in a number of disorders, including bipolar disorder (23,37), schizophrenia (38), QT syndrome (14,39,40), anxiety (13), and post-C D…”

“…NOS1AP has been implicated in a number of disorders, including schizophrenia (12), anxiety (13), QT syndrome (14), and, more recently, breast cancer (15). NOS1AP contains an amino-terminal phosphotyrosine binding (PTB) domain and a carboxyl-terminal PDZ binding motif that directly associates with the PDZ domain of nNOS (16,17).…”

Effects of environmental enrichment in aged mice on anxiety-like behaviors and neuronal nitric oxide synthase expression in the brain

“…nNOS is rich in the limbic system [24], an area that regulates affective behaviors. Moreover, a recent study reported that coupling between nNOS and its carboxy-terminal PDZ ligand (CAPON) in the hippocampus can serve as a target for anxiolytic drugs [25]. Age-associated increases in nNOS protein levels are neurotoxic and subsequently induce abnormalities in affective behaviors.…”

Phosphofructokinase-1 Negatively Regulates Neurogenesis from Neural Stem Cells

“…For lentivirus infection in vivo, as we previously reported, stereotaxic surgery was used to deliver 2 lL of virus suspension (LV-PFK-1-shRNA or LV-Control-shRNA) to the right DG of the hippocampus at coordinates 2.3 mm posterior to bregma, 1.3 mm lateral to the midline, and 2.0 mm below the dura (an intermediate region that has partly overlapping characteristics with dorsal and ventral posterior) [26,27]. The mice were treated with BrdU (50 mg/kg, i.p., four times at 12-h intervals) on days 4 and 5, and sacrificed on days 7 and 14, for immunofluorescence assessment.…”