Neuronal Nitric Oxide Synthase and Post-Translational Modifications in the Development of Central Nervous System Diseases: Implications and Regulation

Figures

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  Figure 1. NO signaling pathways in the brain. The “canonical pathways” of NO signaling are initiated through the stimulation of soluble guanylate cyclase (sGC). The produced cGMP mediates downstream signaling mainly by interacting with PKG, PDE, and cGMP-gated cation channels. The “non-canonical pathways” of NO signaling involve the proteins’ post-translational modifications. Mainly, they are protein nitrosylation, which can lead to the transnitrosylation of other proteins as well as to their denitrosylation by denitrosilases, and protein nitrotyrosination.

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  Figure 2. Representation of the nNOS homodimeric architecture. Each monomer has a carboxy-terminal reductase domain and an amino-terminal oxygenase domain, containing the L-Arg binding site and linked to the PDZ domain. In the reductase domain, electrons via the NADPH-FAD-FMN transport chain reach the heme iron of the opposite monomer oxygenase domain, facilitated by CaM, enabling the oxidation of L-arginine to L-citrulline, accompanied by the release of NO.

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  Figure 3. Representation of the NMDARs-PSD-95-nNOS complex. The red circles represent the Ca2+ ions, the green triangle represents a glycine molecule, and the yellow rectangle represents a glutamate molecule. NMDARs are bound to the PDZ1 domain of the PSD95, and when they are stimulated by the interaction with glycine and glutamate, they allow Ca2+ intracellular influx. This cation binds the nNOS CaM, and the enzyme interacts with the PSD95’s PDZ2 domain by its PDZ β-hairpin motif or with other proteins such as Capon, synthropin, or PSD-93. As a consequence, the enzyme’s activity is stimulated, although an excessive nNOS activation is observed in different SNC diseases, due to the NMDARs’ overstimulation.

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  Figure 4. Chemical structure of the FDA-approved drugs for AD therapy.

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  Figure 5. Chemical structures of approved drugs used in the management of PD.

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  Figure 6. General pharmacophoric structure of an nNOS inhibitor.

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  Figure 7. Chemical structure of nNOS inhibitors.

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  Figure 8. Structure of the peptide-based PSD95-nNOS interaction inhibitor AVLX-144.

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  Figure 9. Chemical structure of small molecules able to selectively bind the nNOS β-finger and of ZL006 and IC87201.