1. Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.69
Figure 4 Ovarian cycle changes proposed to regulate nNOS activity in the hypothalamic preoptic area
Figure 4 | Ovarian cycle changes proposed to regulate nNOS activity in the hypothalamic preoptic area. Ca2+ influx through activated N-methyl-D-aspartate receptors (NMDARs) is largely responsible for the stimulation of neuronal nitric oxide synthase (nNOS) activity via the Ca2+–calmodulin (CaM) complex. The physical interaction of nNOS with NMDAR involves the scaffolding protein postsynaptic density 95 (PSD95) and the assembly of a ternary complex. The phosphorylation (in the figure, indicated by 'P') of nNOS at Ser1412 is responsible for the modulation of its catalytic activity and is regulated across the ovarian cycle (dioestrus is shown in part a; pro-oestrus is shown in part b), reaching maximal levels on the day of pro-oestrus, with nNOS activity being required for the onset of the preovulatory surge in levels of gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH). Three different pathways have been proposed to lead to this phosphorylation of nNOS in the hypothalamic region. First, oestradiol, acting through the oestrogen receptor (ER), promotes the association of nNOS with the NMDAR–PSD95 complex at the plasma membrane, which is required for the activation of nNOS by phosphorylation. Natural fluctuations in levels of oestrogen across the ovarian cycle (that is, low levels in dioestrus and high levels in pro-oestrus) regulate the amount of the nNOS–PSD95–NMDAR ternary complex that is formed. Second, leptin, acting on the leptin receptor (LepR), sustains a basal level of phosphorylation of the nNOS protein in physical association with NMDAR, possibly via the phosphoinositide 3-kinase (PI3K)–protein kinase B (PKB) pathway. Last, on pro-oestrus, oestradiol-activated kisspeptin–kisspeptin receptor (GPR54) signalling is thought to promote the phosphorylation of nNOS protein at Ser1412 via the PI3K–PKB pathway. In the figure, the question marks indicate hypothetical pathways. AVPV, anteroventral periventricular nucleus; l-Arg, l-arginine; l-Cit, l-citrulline; MePO, median preoptic nucleus; OVLT, organum vasculosum laminae terminalis; 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
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