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 Grandy, Thomas (Tom) Scanlan, Oline Ronnekleiv, Martin Kelly

Research output: Contribution to journalArticle

373 Citations (Scopus)

Abstract

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
Volume23
Issue number29
StatePublished - Oct 22 2003

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G-Protein-Coupled Receptors
Protein Kinase C
Estrogens
Neurons
Estrogen Receptors
GABAergic Neurons
Pro-Opiomelanocortin
Dopaminergic Neurons
GABA-B Receptors
Inwardly Rectifying Potassium Channel
Selective Estrogen Receptor Modulators
Membranes
Type C Phospholipases
Patch-Clamp Techniques
Cyclic AMP-Dependent Protein Kinases
GTP-Binding Proteins
Synaptic Transmission
gamma-Aminobutyric Acid
Opioid Analgesics
Reverse Transcription

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C. / Qiu, Jian; Bosch, Martha A.; Tobias, Sandra C.; Grandy, David; Scanlan, Thomas (Tom); Ronnekleiv, Oline; Kelly, Martin.

In: Journal of Neuroscience, Vol. 23, No. 29, 22.10.2003, p. 9529-9540.

Research output: Contribution to journalArticle

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AU - Tobias, Sandra C.

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AU - Ronnekleiv, Oline

AU - Kelly, Martin

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