Roles of estrogen receptor α and androgen receptor in the regulation of neuronal nitric oxide synthase

Abstract

In brain and peripheral tissues, steroid hormones regulate nitric oxide synthase (nNOS). We asked whether estrogen receptor-alpha (ERalpha) and/or androgen receptor (AR) regulated nNOS immunoreactivity in mouse brain. First, we quantified cells singly labeled for nNOS immunoreactivity or labeled dually with ERalpha-immunoreactive (-ir) or AR-ir cells in the nucleus accumbens (Acb), preoptic area (POA), bed nucleus of the stria terminalis (BNST), posterior dorsal and posterior ventral regions of the medial amygdala (MePD and MePV, respectively), and paraventricular nucleus (PVN). The POA and MePD contained the greatest number of double-labeled cells. More nNOS-ir cells were colabeled with ERalpha immunoreactivity compared with AR immunoreactivity. Next, by using a double mutant mouse in which males lacked functional ERalpha, AR, or both, we investigated the roles of these steroid receptors in nNOS-ir cell numbers and immunoreactive area staining under testosterone (T) and estradiol (E2) conditions. Our data show that functional ERalpha is correlated with more nNOS-ir cells under T conditions and more immunoreactive area staining in the POA under both T and E2 conditions. However, ERalpha decreases nNOS-ir cell number in the BNST under E2 treatment. In summary, the data suggest that AR has organizational actions on nNOS-ir cell numbers in the MePV, that interactions between ERalpha and AR genes occur in PVN, and that sex differences in nNOS-ir area staining are limited to the POA. Thus, we show that ERalpha and AR interact to regulate nNOS in male and female brain in a site-specific manner.

Sexual behavior in male rodents

“…MPOA lesions severely impaired copulation in male mice, as in other species (reviewed in Hull et al, 2006). ERαKO had less nNOS-ir in the MPOA than WT or Tfm mice; therefore, E up-regulates nNOS-ir in mice (Scordalakes et al, 2002) as well as in rats.…”

Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

“…Accordingly, another recent study has demonstrated that an agonist of the NMDA-type glutamate receptor, which triggers puberty, ovulation, and GnRH secretion in both rodents (Urbanski and Ojeda, 1990;Brann and Mahesh, 1991) and primates (Plant et al, 1989;Claypool et al, 2000), is capable of activating the reproductive axis in both Kiss-and Gpr54-null mice, and that these effects may involve nNOS neurons (d'Anglemont de . Since most nNOS neurons of the preoptic region express the NMDA receptor (d'Anglemont de Tassigny et al, 2007a) and estrogen receptor ␣ (Scordalakes et al, 2002;Sato et al, 2005), both of which are critical for the estrogen positive-feedback effect on GnRH neurons (Brann and Mahesh, 1991;Wintermantel et al, 2006) and nNOS activity (d'Anglemont de Tassigny et al, 2007a, it is tempting to speculate that nNOS neurons may be involved in the cellular mechanisms underlying compensation in animals in which neurons mediating kisspeptin/GPR54 signaling are absent (Mayer and Boehm, 2011). Estrogens may indeed regulate Intriguingly, our immunofluorescence experiments demonstrated that the systemic administration of kisspeptin selectively induces nNOS phosphorylation in an area proximal to the OVLT, a brain area devoid of a blood-brain barrier (Broadwell and Brightman, 1976;Ciofi et al, 2009) and containing numerous kisspeptin fibers and nNOS neurons (present paper), and to which GnRH neurons have recently been shown to extend dendrites (Herde et al, 2011;Prevot, 2011).…”

Coupling of Neuronal Nitric Oxide Synthase to NMDA Receptors via Postsynaptic Density-95 Depends on Estrogen and Contributes to the Central Control of Adult Female Reproduction

“…In the preoptic region of the hypothalamus, most NMDA receptor-expressing neurons also contain estrogen receptor ␣ (Chakraborty et al, 2003), which is not only localized to cell nuclei but also found in perikaryal cy- toplasm and dendrites (Blaustein, 1992;Blaustein et al, 1992). In fact, up to 90% of nNOS neurons of the preoptic region were shown to express estrogen receptor ␣ (Scordalakes et al, 2002;Sato et al, 2005). Together with our results showing that virtually all nNOS neurons express NMDA receptor NR2B subunit, these studies suggest that most nNOS neurons in the preoptic region also contain estrogen receptors.…”