Estrogen modulation of K+ channel activity in hypothalamic neurons involved in the control of the reproductive axis

Martin J. Kelly, Oline K. Rønnekleiv, Nurhadi Ibrahim, Andre H. Lagrange, Edward J. Wagner

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


Here we report on the progress we have made in elucidating the mechanisms through which estrogen alters synaptic responses in hypothalamic neurons. We examined the modulation by estrogen of the coupling of various receptor systems to inwardly rectifying and small conductance, Ca2+-activated K+ (SK) channels. We used intracellular sharp-electrode and whole-cell recordings in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly rectifying K+ (GIRK) channels in β-endorphin neurons, manifest by a reduction in the potency of μ-opioid receptor agonists to hyperpolarize these cells. This effect is blocked by inhibitors of protein kinase A and protein kinase C. Estrogen also uncouples γ-aminobutyric acid (GABA)B receptors from the same population of GIRK channels coupled to μ-opioid receptors. At 24 h after steroid administration, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area (POA) is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these POA GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of both arcuate and POA neurons, among which gonadotropin-releasing hormone (GnRH) neurons are particularly sensitive. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity that serves to control the excitability of hypothalamic neurons involved in regulating the reproductive axis.

Original languageEnglish (US)
Pages (from-to)447-456
Number of pages10
Issue number6
StatePublished - 2002


  • Estrogen
  • GABA
  • K Channel
  • Norepinephrine
  • Protein kinase
  • β-Endorphin

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Endocrinology
  • Pharmacology
  • Clinical Biochemistry
  • Organic Chemistry


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