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-,nNOS-,nNOS-,nNOS-and nNOS-2.Monomer of nNOS is inactive,and dimer is the active form.Dimerization requires tetrahydrobiopterin （BH 4）,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/calmodulindependent 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.
