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

Abstract

Besides its quintessential role in reproduction, 17β-estradiol (E2) is a potent anorexigenic hormone. E2 and the selective Gq-coupled membrane estrogen receptor (Gq-mER) ligand STX rapidly increase membrane excitability in proopiomelanocortin (POMC) neurons by desensitizing the coupling of GABAB receptors to G protein-coupled inwardly rectifying K+ channels (GIRKs), which upon activation elicit a hyperpolarizing outward current. However, it is unknown whether E2 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 GABAB 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 p110β subunit inhibitor TGX-221. The ERα-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 E2 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 ERα by E2 attenuates it. These findings demonstrate a clear functional dichotomy of rapid E2 membrane-initiated signaling via ERα vs. Gq-mER in a CNS neuron vital for regulating energy homeostasis.