Fig. 7.

Proposed model for the downregulation of nNOS by posttranslational regulation in the PVN in CHF. In CHF, carboxy-terminal PDZ ligand of nNOS (CAPON) and PIN are overexpressed due to increased ANG II levels and AT₁ receptors in the PVN. Increased CAPON competes with postsynaptic density (PSD)95 for binding to nNOS and sequesters nNOS therefore decreasing N-methyl-d-aspartic acid receptor (NMDAR)/PSD95/nNOS complexes. Binding of PIN to nNOS in CHF destabilizes nNOS dimers, which renders nNOS catalytically inactive, by interfering with either the assembly or dimer stability. Inactive nNOS monomers are susceptible to ubiquitination and subsequent proteasomal degradation. This results in decreased levels of nNOS in the PVN of CHF rats. A decreased level of nNOS reduces NO production in the PVN during CHF causing an increase in sympathetic nerve activity (SNA).