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.
神经元型一氧化氮合酶(neuronal nitric oxide synthase, nNOS)主要表达于神经元, 在星形胶质细胞和神经干细胞中也有一定水平的表达。 不同的mRNA拼接形式产生了nNOS 蛋白的5 种亚型,包括nNOS-α、 nNOS-β、 nNOS-μ、 nNOS-γ 和nNOS-2。 nNOS 单体不具催化活性, 二聚体是其活性形式。 nNOS 单体发生二聚化需要四氢生物蝶呤、 血红素以及L-精氨酸的结合。 nNOS的表达在很大程度上依赖于cAMP反应元件结合蛋白的活化, 其催化活性的调节与热休克蛋白90/ 热休克蛋白70、 钙调节蛋白、 PIN 蛋白, 以及自身Ser847 和Ser1412 位点的磷酸化和脱磷酸化相关。 能与nNOS相互作用的蛋白主要有9 种, 包括突触后密度蛋白95 (post-synaptic density protein 95, PSD95)、 CALM、 CAMKIIA、 DLG4、 DLG2、 PFK-M、 CAPON、 syntrophin 和 dynein 轻链。 其中PSD95、 CAPON 和 PFK-M 是神经元中最重要的nNOS 调节蛋白。 PSD95 与nNOS 的相互作用能介导突触形成, 并参与N- 甲基-D- 天冬氨酸诱导的神经元死亡。 此外, nNOS 来源的一氧化氮还与多种神经病理状态早期突触丢失导致的认知、 运动功能缺陷相关, 并对生理病理的成年神经发生起负调控作用。