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Review
. 2015 May;29(5):645-57.
doi: 10.1210/me.2014-1397. Epub 2015 Mar 9.

Minireview: neural signaling of estradiol in the hypothalamus

Martin J Kelly  1 , Oline K Rønnekleiv
Affiliations
Review

Minireview: neural signaling of estradiol in the hypothalamus

Martin J Kelly et al. Mol Endocrinol. 2015 May.
No abstract available

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Figures

Figure 1.
Figure 1.
Cellular actions of E2 in POMC neurons. Schematic overview of the E2-mediated modulation of Gαi,o-coupled (μ-opioid and GABAB) receptors via a membrane-associated receptor (mER) in hypothalamic POMC neurons. E2 binds to a mER that is Gαq-coupled to activate phospholipase C (PLC) and catalyzes the hydrolysis of membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) to inositol 1,4,5 triphosphate (IP3) and diacylglycerol (DAG). Calcium is released from intracellular stores (endoplasmic reticulum) by IP3, and DAG activates PKCδ. Through phosphorylation, adenylyl cyclase VII (AC VII) activity is up-regulated by PKC. The generation of cAMP activates protein kinase A (PKA), which can uncouple μ-opioid (μ) and GABAB receptors from their signaling pathway through phosphorylation of a downstream effector molecule (eg, G protein-coupled, inwardly rectifying K+, GIRK, channels). PKA can also potentially phosphorylate other channels (eg, canonical transient receptor potential [TRPC] channels) to alter their function (data not shown). In addition, the membrane-initiated E2 signaling through PKA can phosphorylate cAMP-responsive element binding protein (pCREB), which can alter gene transcription through its interaction with the cAMP response element (CRE). Therefore, the rapid membrane-initiated signaling can alter gene expression in an ERE-independent fashion.
Figure 2.
Figure 2.
E2 and STX attenuate the body weight gain in female guinea pigs after ovariectomy. Ovariectomized female guinea pigs were given bidaily sc injections of vehicle, E2 benzoate (EB), or STX starting on day 0 (1 week after ovariectomy). Both EB and STX significantly decreased body weight gain (two-way ANOVA overall significant effect, P < .001), and post hoc Newman-Keuls analysis revealed daily significant differences between EB and vehicle-treated, and STX and oil-treated groups (**, P < .01). (Reproduced from Roepke et al [167].)
Figure 3.
Figure 3.
Effects of E2 and STX on hypothalamic POMC and NPY/AgRP neurons. Summary of how E2 excites POMC neurons and inhibits NPY/AgRP neurons via a Gαq-mER-mediated signaling pathway to regulate metabolism (A). Activation of the Gαq pathway attenuates the coupling of the GABAB receptor to GIRK channel activation in POMC neurons, thereby increasing the excitability, but enhances the GABAB receptor activation of GIRK channels in NPY/AgRP neurons, thereby decreasing their excitability. In NPY/AgRP neurons, ERα is also associated with the membrane, and its activation leads to attenuation of the GABAB receptor coupling to GIRK channels (B), which is hypothesized to be involved in the control of reproduction (see text for more details).
Figure 4.
Figure 4.
E2 and STX reduce core body temperature (Tc) of ovariectomized female guinea pigs. Similar to E2 benzoate (EB)-treated females (8 μg/kg), STX (6 mg/kg) significantly decreased Tc compared with the propylene glycol vehicle (PPG). One week after ovariectomy, females were given daily sc injections of ligands at 10 am on M, W, and F. The data are presented as the mean ± SEM for each hour of the day averaged over 3 weeks of temperature probe recordings (ie, 3 weeks of temperature probe [SubCue DataLogger] measurements were collapsed down to a 24-h period). The data were analyzed using a two-way ANOVA (P < .05, F = 4.787, df = 2) with post hoc Newman-Keuls multiple comparison tests. All data points for both STX and EB were significantly different from vehicle (P < .01) except for the STX 2 pm to 4 pm hour time points (P < .05). The solid bar above the x-axis represents lights off or nighttime. (Reproduced from Roepke et al [168].)
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