Estrogen Modulation of G-Protein-Coupled Receptor Activation of Potassium Channels in the Central Nervous System

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101 Scopus citations

Abstract

Estrogen rapidly alters the excitability of hypothalamic neurons that are involved in regulating numerous homeostatic functions including reproduction, stress responses, feeding, and motivated behaviors. Neurosecretory neurons, such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons, such as pro-opiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons, are among those involved. We have identified membrane-initiated, rapid-signaling pathways through which 17β-estradiol (E2) alters synaptic responses in these neurons using whole-cell patch recording in hypothalamic slices from ovariectomized female guinea pigs. E2 rapidly uncouples μ-opioid and GABAB receptors from G-protein-gated inwardly rectifying K+ (GIRK) channels in POMC and dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to activate these channels. These effects are mimicked by the selective E2 receptor modulators raloxifene and 4OH-tamoxifen, the membrane impermeable E2-bovine serum albumin (BSA), but not by 17α-estradiol. Furthermore, the anti-estrogen ICI 182,780 antagonizes these rapid effects of E2. Inhibitors of phospholipase C, protein kinase C, and protein kinase A block the actions of E2, indicating that the E2 receptor is G-protein-coupled to activation of this cascade. Conversely, estrogen enhances the efficacy of α1-adrenergic receptor agonists to inhibit apamin-sensitive small-conductance, Ca2+-activated K+ (SK) currents in preoptic GABAergic neurons; it does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate that E2 can modulate K+ channels in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions through multiple intracellular signaling pathways.

Original languageEnglish (US)
Pages (from-to)6-9
Number of pages4
JournalAnnals of the New York Academy of Sciences
Volume1007
DOIs
StatePublished - Jan 1 2003

Keywords

  • Dopamine
  • GABA
  • K channel
  • Lipase C
  • Norepinephrine
  • POMC
  • Phospho
  • Protein kinase A
  • Protein kinase C

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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