Neuronal nitric oxide synthase (nNOS) is mainly expressed in neurons, to some extent in astrocytes and neuronal stem cells. The alternative splicing of nNOS
mRNA generates 5
isoforms of nNOS, including nNOS-α, nNOS-β, nNOS-µ, nNOS-γ and nNOS-2. Monomer of nNOS is inactive, and dimer is the active form. Dimerization requires
tetrahydrobiopterin (BH4),
heme and
L-arginine binding. Regulation of nNOS expression relies largely on
cAMP response element-binding protein (CREB) activity, and nNOS activity is regulated by
heat shock protein 90 (HSP90)/HSP70,
calmodulin (CaM), phosphorylation and dephosphorylation at Ser847 and Ser1412, and the
protein inhibitor of nNOS (PIN). There are primarily 9 nNOS-interacting
proteins, including post-synaptic density
protein 95 (PSD95),
clathrin assembly
lymphoid leukemia (CALM),
calcium/calmodulin-dependent protein kinase II alpha (CAMKIIA), Disks large homolog 4 (DLG4), DLG2,
6-phosphofructokinase, muscle type (PFK-M), carboxy-terminal PDZ
ligand of nNOS (CAPON)
protein,
syntrophin and
dynein light chain (LC). Among them, PSD95, CAPON and PFK-M are important nNOS adapter
proteins in neurons. The interaction of PSD95 with nNOS controls synapse formation and is implicated in
N-methyl-D-aspartic acid-induced neuronal death. nNOS-derived NO is implicated in synapse loss-mediated early cognitive/motor deficits in several neuropathological states, and negatively regulates neurogenesis under physiological and pathological conditions.