Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Carrier Proteins / metabolism*
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / metabolism
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Cyclic GMP / metabolism
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Guanine Nucleotides / metabolism
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Mice
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Mice, Knockout
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Molecular Sequence Data
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Monomeric GTP-Binding Proteins / genetics*
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Monomeric GTP-Binding Proteins / metabolism*
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Neurons / cytology
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Neurons / metabolism
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Nitric Oxide / metabolism
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Synthase / deficiency
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase / metabolism*
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Nitric Oxide Synthase Type I
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Organ Specificity
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Protein Binding / genetics
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Rats
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Receptors, N-Methyl-D-Aspartate / metabolism
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Sulfhydryl Compounds / metabolism
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ras Proteins / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Guanine Nucleotides
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NOS1AP protein, human
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NOS1AP protein, rat
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Nitric Oxide Donors
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Nos1ap protein, mouse
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RNA, Messenger
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Receptors, N-Methyl-D-Aspartate
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Sulfhydryl Compounds
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Nitric Oxide
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type I
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Nos1 protein, mouse
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Nos1 protein, rat
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GTP-Binding Proteins
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Rasd1 protein, mouse
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Monomeric GTP-Binding Proteins
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ras Proteins
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Cyclic GMP