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

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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)6-16
Number of pages11
JournalAnnals of the New York Academy of Sciences
Volume1007
DOIs
StatePublished - 2003

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Potassium Channels
Neurology
G-Protein-Coupled Receptors
Neurons
Estrogens
Central Nervous System
Chemical activation
Modulation
Pro-Opiomelanocortin
Gonadotropin-Releasing Hormone
GABAergic Neurons
Dopaminergic Neurons
Opioid Receptors
Estradiol
Dopamine
Inwardly Rectifying Potassium Channel
Apamin
Aminobutyrates
Adrenergic Agonists
Membranes

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

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title = "Estrogen Modulation of G-Protein-Coupled Receptor Activation of Potassium Channels in the Central Nervous System",
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.",
keywords = "Dopamine, GABA, K channel, Lipase C, Norepinephrine, Phospho, POMC, Protein kinase A, Protein kinase C",
author = "Martin Kelly and Jian Qiu and Oline Ronnekleiv",
year = "2003",
doi = "10.1196/annals.1286.001",
language = "English (US)",
volume = "1007",
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journal = "Annals of the New York Academy of Sciences",
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TY - JOUR

T1 - Estrogen Modulation of G-Protein-Coupled Receptor Activation of Potassium Channels in the Central Nervous System

AU - Kelly, Martin

AU - Qiu, Jian

AU - Ronnekleiv, Oline

PY - 2003

Y1 - 2003

N2 - 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.

AB - 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.

KW - Dopamine

KW - GABA

KW - K channel

KW - Lipase C

KW - Norepinephrine

KW - Phospho

KW - POMC

KW - Protein kinase A

KW - Protein kinase C

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U2 - 10.1196/annals.1286.001

DO - 10.1196/annals.1286.001

M3 - Article

VL - 1007

SP - 6

EP - 16

JO - Annals of the New York Academy of Sciences

JF - Annals of the New York Academy of Sciences

SN - 0077-8923

ER -