The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17β-estradiol

Abstract

Smith AW, Bosch MA, Wagner EJ, Rønnekleiv OK, Kelly MJ. The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17␤-estradiol. Am J Physiol Endocrinol Metab 305: E632-E640, 2013. First published July 9, 2013; doi:10.1152/ajpendo.00281.2013.-Besides its quintessential role in reproduction, 17␤-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (GqmER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K ϩ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E 2 and STX can modulate GABAB signaling in neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons. We used single-cell RT-PCR and whole cell patch clamping with selective pharmacological reagents to show that NPY/ AgRP cells of mice express the GABAB-R1 and -R2 receptors and are hyperpolarized by the GABA B agonist baclofen in an E2-dependent manner. In males, E2 rapidly attenuated the coupling of GABAB receptors to GIRKs, which was blocked by the general PI3K inhibitors wortmannin and LY-294002 or the selective p110␤ subunit inhibitor TGX-221. The ER␣-selective agonist propyl pyrazole triol mimicked the effects of E2. STX, in contrast, enhanced the GABAB response in males, which was abrogated by the estrogen receptor (ER) antagonist ICI 182,780. In gonadectomized mice of both sexes, E2 enhanced or attenuated the GABAB response in different NPY/AgRP cells. Coperfusing wortmannin with E 2 or simply applying STX always enhanced the GABAB response. Thus, in NPY/AgRP neurons, activation of the Gq-mER by E2 or STX enhances the GABAergic postsynaptic response, whereas activation of ER␣ by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membraneinitiated signaling via ER␣ vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.NPY; AgRP; estradiol; feeding TWO CELL POPULATIONS residing within the arcuate nucleus (ARC) of the hypothalamus compose a critical circuit for regulating energy homeostasis: neuropeptide Y (NPY)/agoutirelated peptide (AgRP) and proopiomelanocortin (POMC) neurons (12). Selective stimulation of NPY/AgRP neurons via optogenetics evokes intense feeding (3), and ablation of these neurons in adults causes starvation, evidently due to loss of inhibitory signaling to the brain stem (24,52,53). Similar and other approaches have revealed that POMC cells control the exact opposite actions in energy balance (3,13,32,39,50,54).These two populations of neurons are thought to regulate feeding through sensing blood-borne metabolic factors and then synaptically releasing their expressed peptides or derivatives into various brain regions such as the paraventricular nucleus and lateral hypothalamus (12).Estrogens, such as 17␤-estradiol (E 2 ), regulate energy balance in females and...

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Sex differences in cannabinoid-regulated biology: A focus on energy homeostasis

“…Activation of these receptors by estradiol elicits a signal transduction cascade involving phosphatidylinositol-3-kinase (PI3K), protein kinase C (PKC), protein kinase A (PKA) and neuronal nitric oxide synthase (nNOS) to unravel the coupling of the presynaptic CB1 receptors to their effector systems (Borgquist et al, 2015a; Mela et al, 2015; Washburn et al, 2013) (Figure 1). PI3K is a signaling molecule that is activated upon both ERα and ERβ stimulation (Gingerich and Krukoff, 2008; Smith et al, 2013), as well as by other anorexigenic hormones such as leptin and insulin (Hill et al, 2008; Mela et al, 2015; Qiu et al, 2014), within various elements of the hypothalamic feeding circuitry. PI3K signaling in murine POMC neurons plays an important role in the ERα-mediated regulation of appetite and insulin sensitivity (Zhu et al, 2015).…”

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“…Within the dorsal hippocampus, this E 2 /mGluR signaling is essential for E 2 and agonists of ERα and ERβ to enhance object recognition and spatial memory consolidation (Boulware et al, 2013). Rapid non-classical effects of estrogens may also be mediated by putative plasma membrane receptors, including GPER (GPR30) (Filardo et al, 2007), Gq-mER (Smith et al, 2013), and ER-X (Toran-Allerand et al, 2002). GPER is the most well studied of these receptors, and has been identified within hippocampal dendritic spines and in hippocampally-projecting basal forebrain cholinergic neurons (Hammond and Gibbs, 2011; Hammond et al, 2011; Srivastava and Evans, 2013).…”