Phosphorylation of N-Methyl-d-Aspartic Acid Receptor-Associated Neuronal Nitric Oxide Synthase Depends on Estrogens and Modulates Hypothalamic Nitric Oxide Production during the Ovarian Cycle

Within the preoptic region, nitric oxide (NO) production varies during the ovarian cycle and has the ability to impact hypothalamic reproductive function. One mechanism for the regulation of NO release mediated by estrogens during the estrous cycle includes physical association of the calcium-activated neuronal NO synthase (nNOS) enzyme with the glutamate N-methyl-d-aspartate (NMDA) receptor channels via the postsynaptic density 95 scaffolding protein. Here we demonstrate that endogenous variations in estrogens levels during the estrous cycle also coincide with corresponding changes in the state of nNOS Ser1412 phosphorylation, the level of association of this isoform with the NMDA receptor/postsynaptic density 95 complex at the plasma membrane, and the activity of NO synthase (NOS). Neuronal NOS Ser1412 phosphorylation is maximal on the afternoon of proestrus when both the levels of estrogens and the physical association of nNOS with NMDA receptors are highest. Estradiol mimicked these effects in ovariec...