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.