Classically, 17β-estradiol (E₂) is thought to control homeostatic functions such as reproduction, stress responses, feeding, sleep cycles, temperature regulation, and motivated behaviors through transcriptional events. Although it is increasingly evident that E₂ can also rapidly activate kinase pathways to have multiple downstream actions in CNS neurons, the receptor(s) and the signal transduction pathways involved have not been identified. We discovered that E₂ can alter μ-opioid and GABA neurotransmission rapidly through nontranscriptional events in hypothalamic GABA, proopiomelanocortin (POMC), and dopamine neurons. Therefore, we examined the effects of E₂ in these neurons using whole-cell recording techniques in ovariectomized female guinea pigs. E₂ reduced rapidly the potency of the GABA_B receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K⁺ channels in hypothalamic neurons. These effects were mimicked by the membrane impermeant E₂-BSA and selective estrogen receptor modulators, including a new diphenylacrylamide compound, STX, that does not bind to intracellular estrogen receptors α or β, suggesting that E₂ acts through a unique membrane receptor. We characterized the coupling of this estrogen receptor to a Gα_q-mediated activation of phospholipase C, leading to the upregulation of protein kinase Cδ and protein kinase A activity in these neurons. Moreover, using single-cell reverse transcription-PCR, we identified the critical transcripts, PKCδ and its downstream target adenylyl cyclase VII, for rapid, novel signaling of E₂ in GABA, POMC, and dopamine neurons. Therefore, this unique G_q-coupled estrogen receptor may be involved in rapid signaling in hypothalamic neurons that are critical for normal homeostatic functions.