Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C

Jian Qiu, Martha A. Bosch, Sandra C. Tobias, David K. Grandy, Thomas S. Scanlan, Oline K. Rønnekleiv, Martin J. Kelly

Research output: Contribution to journalArticle

377 Scopus citations


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 GABAB receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K+ channels in hypothalamic neurons. These effects were mimicked by the membrane impermeant E 2-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 Gαq-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 E 2 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.

Original languageEnglish (US)
Pages (from-to)9529-9540
Number of pages12
JournalJournal of Neuroscience
Issue number29
StatePublished - Oct 22 2003



  • Dopamine
  • GABA receptor
  • GAD
  • GIRK
  • POMC
  • SERMs

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this