Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.69 Figure 1 Splice variants of nNOS and the main activatory mechanism of nNOSα Figure 1 | Splice variants of nNOS and the main activatory mechanism of nNOSα. a | Neuronal nitric oxide synthase isoform-α (nNOSα) mRNA contains 29 exons, and its translation results in a protein product of 160 kDa. The nNOSβ and nNOSγ variants initiate their translation through different first exons, skipping exon 2, which contains the PDZ domain. All three nNOS isoforms contain oxygenase and reductase domains, as well as calmodulin and tetrahydrobiopterin domains. Conversely, both nNOSβ and nNOSγ isoforms, in addition to the lack of the PDZ domain, also lack the regions permitting interaction with NOS-interacting protein (NOSIP) and protein inhibitor of NOS (PIN). Alternative splicing events of nNOSβ and nNOSγ mRNAs generate 136 kDa and 125 kDa proteins, respectively. b | The translocation of nNOSα from the cytosol to the membrane and its physical interaction with the NR2B subunit of the N-methyl-D-aspartate receptor (NMDAR) via its PDZ domain (red bar) involve the scaffolding protein postsynaptic density 95 (PSD95) and the assembly of a ternary complex, nNOS–PSD95–NMDAR. The binding of glutamate to the NMDAR enables Ca2+ entry into the neuron, which activates nNOSα through calmodulin (CaM) binding, and leads to the production of NO (which is formed enzymatically from l-arginine (l-Arg) in equimolar amounts with l-citrulline (l -Cit)). In parallel, membrane-tethered nNOS is also subjected to post-transcriptional modifications (such as phosphorylation via protein kinase B (PKB)) that modulate its catalytic activity. PIP3, phosphatidylinositol 3,4,5-triphosphate. Chachlaki, K. et al. (2017) The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.69