Hippocampal overexpression of Nos1ap promotes endophenotypes related to mental disorders

Abstract Nitric oxide synthase 1 adaptor protein (NOS1AP; previously named CAPON) is linked to the glutamatergic postsynaptic density through interaction with neuronal nitric oxide synthase (nNOS). NOS1AP and its interaction with nNOS have been associated with several mental disorders. Despite the high levels of NOS1AP expression in the hippocampus and the relevance of this brain region in glutamatergic signaling as well as mental disorders, a potential role of hippocampal NOS1AP in the pathophysiology of these disorders has not been investigated yet. To uncover the function of NOS1AP in hippocampus, we made use of recombinant adeno-associated viruses to overexpress the murine Nos1ap isoform in the hippocampus of mice. We investigated these mice for changes in gene expression, electrophysiology, neuronal morphology, and relevant behavioral phenotypes. We found that overexpression of hippocampal Nos1ap markedly increased the interaction of nNOS with PSD-95, reduced dendritic spine density and changed dendritic spine morphology without affecting basic synaptic signaling properties at CA1 synapses. At the behavioral level, we observed an impairment in social interaction and social memory, as well as decreased spatial working memory capacity. Our data provide a mechanistic explanation for a highly selective and specific contribution of hippocampal NOS1AP and its interaction with the glutamatergic postsynaptic density to cross-disorder pathophysiology. Our findings allude to therapeutic relevance due to the druggability of this molecule.

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Cloning and Characterization of Postsynaptic Density 93, a Nitric Oxide Synthase Interacting Protein

Journal of Neuroscience ◽

10.1523/jneurosci.16-23-07407.1996 ◽

1996 ◽

Vol 16 (23) ◽

pp. 7407-7415 ◽

Cited By ~ 216

Author(s):

Jay E. Brenman ◽

Karen S. Christopherson ◽

Sarah E. Craven ◽

Aaron W. McGee ◽

David S. Bredt

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Postsynaptic Density ◽

Interacting Protein ◽

Oxide Synthase

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‘Social distancing’ of the neuronal nitric oxide synthase from its adaptor protein causes arrhythmogenic trigger-substrate interactions in long QT syndrome

Cardiovascular Research ◽

10.1093/cvr/cvaa179 ◽

2020 ◽

Author(s):

Andrew Tieu ◽

Fadi G Akar

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Long Qt Syndrome ◽

Adaptor Protein ◽

Neuronal Nitric Oxide Synthase ◽

Long Qt ◽

Substrate Interactions ◽

Social Distancing ◽

Qt Syndrome ◽

Oxide Synthase

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Interaction of the endothelial nitric oxide synthase with the CAT-1 arginine transporter enhances NO release by a mechanism not involving arginine transport

Biochemical Journal ◽

10.1042/bj20041005 ◽

2005 ◽

Vol 386 (3) ◽

pp. 567-574 ◽

Cited By ~ 40

Author(s):

Chunying LI ◽

Wei HUANG ◽

M. Brennan HARRIS ◽

Jonathan M. GOOLSBY ◽

Richard C. VENEMA

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Adaptor Protein ◽

No Production ◽

Arginine Transport ◽

No Release ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

eNOS (endothelial nitric oxide synthase) catalyses the conversion of L-arginine into L-citrulline and NO. Evidence has been presented previously that eNOS is associated with the CAT (cationic amino acid transporter)-1 arginine transporter in endothelial caveolae, and it has been proposed that eNOS–CAT-1 association facilitates the delivery of extracellular L-arginine to eNOS. Definitive proof of a protein–protein interaction between eNOS and CAT-1 is lacking, however, and it is also unknown whether the two proteins interact directly or via an adaptor protein. In the present study, we raised a polyclonal antibody against CAT-1, and show using reciprocal co-immunoprecipitation protocols that eNOS and CAT-1 do indeed form a complex in BAECs (bovine aortic endothelial cells). In vitro binding assays with GST (glutathione S-transferase)–CAT-1 fusion proteins and eNOS show that the two proteins interact directly and that no single CAT-1 intracellular domain is sufficient to mediate the interaction. Overexpression of CAT-1 in BAECs by adenoviral-mediated gene transfer results in significant increases in both L-arginine uptake and NO production by the cells. However, whereas increased L-arginine transport is reversed completely by the CAT-1 inhibitor, L-lysine, increased NO release is unaltered, suggesting that NO production in this in vitro model is independent of CAT-1-mediated transport. Furthermore, eNOS enzymic activity is increased in lysates of CAT-1-overexpressing cells accompanied by increased phosphorylation of eNOS at Ser-1179 and Ser-635, and decreased association of eNOS with caveolin-1. Taken together, these data suggest that direct interaction of eNOS with CAT-1 enhances NO release by a mechanism not involving arginine transport.

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