Modulation of hypothalamic neuronal activity through a novel G-protein-coupled estrogen membrane receptor

Abstract

Estrogens are involved in the hypothalamic control of multiple homeostatic functions including reproduction, stress responses, energy metabolism, sleep cycles, temperature regulation, and motivated behaviors. The actions of 17β-estradiol (E 2 ) in the brain have been attributed to the activation of estrogen receptors α and β, as well as G-protein coupled or other membraneassociated estrogen receptors. Recently, we have identified a putative membrane-associated estrogen receptor that is coupled to desensitization of GABA B receptors in guinea pig and mouse hypothalamic neurons including proopiomelanocortin (POMC) neurons. We have synthesized a new nonsteroidal compound, STX, which selectively targets the Gαq-coupled phospholipase Cprotein kinase C-protein kinase A pathway, and have established that STX is more potent than E 2 in mediating this desensitization in an ICI 182, 780-sensitive manner in both guinea pig and mouse neurons. Both E 2 and STX are fully efficacious in estrogen receptor α, β knockout mice. Finally, we observed that the putative membrane-associated estrogen receptor is different from GPR30 in arcuate neurons using whole-cell patch recording in hypothalamic slices from GPR30 knockout mice. Collectively, these findings suggest that the mER is distinct from ERα, ERβ or GPR30.

17β-Estradiol Rapidly Increases KATP Activity in GnRH via a Protein Kinase Signaling Pathway

“…The GPR30 agonist G-1 has been shown to increase Ca 2ϩ oscillations and GnRH release from cultured GnRH neurons derived from the monkey olfactory placode region (20). However, STX does not activate GPR30 in native hypothalamic neurons (40). Therefore, the effects of STX are mediated via a receptor (mER) that is distinct from ER␣, ER␤, or GPR30.…”

Rapid effects of estrogens on behavior: Environmental modulation and molecular mechanisms

“…So far there is little direct evidence for GPR30 mediated effects on behavior (but see Anchan et al, 2014 and Hawley et al, 2014). An alternative membrane receptor (dubbed Gq-mER) has been identified in hypothalamic neurons that mediates rapid estrogen modulation of phospholipase C activity [25]. Hypothalamic neurons expressing mER coexpress POMC or dopamine, which regulate energy balance.…”

Expression of G protein estrogen receptor (GPER) on membrane of mouse oocytes during maturation

“…In addition to these classic genomic actions by activation of nuclear estrogen receptor (nER) and resulting in changes of transcription rates of a large number of estrogen-responsive genes, some estrogen receptors associated with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen through nongenomic estrogen actions [1,2]. Several cell and tissue models have been found in hypothalamic neurons, pancreatic islets, marophages, and human breast cancer cells, are not involved in nER but mediated by novel membrane estrogen receptor (mER) [3][4][5][6]. One purported membrane or endoplasmic reticulum ER is the G protein coupled receptor 30 (GPR30) [7][8][9].…”