Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)

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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. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca2+-activated K+ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K + (GIRK) channels in POMC neurons and GABAB receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24h following steroid administration in vivo, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α 1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.

Original languageEnglish (US)
Pages (from-to)187-193
Number of pages7
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume83
Issue number1-5
DOIs
StatePublished - Dec 2002

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Potassium Channels
Neurology
G-Protein-Coupled Receptors
Neurons
Estrogens
Central Nervous System
Chemical activation
Inwardly Rectifying Potassium Channel
GABAergic Neurons
Pro-Opiomelanocortin
Steroids
Gonadotropin-Releasing Hormone
Dopaminergic Neurons
Opioid Receptors
Dopamine
Apamin
Aminobutyrates
Calcium-Activated Potassium Channels
Adrenergic Agonists
Preoptic Area

Keywords

  • Dopamine
  • GABA
  • K channel
  • Norepinephrine
  • POMC
  • Protein kinase

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

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title = "Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)",
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. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca2+-activated K+ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K + (GIRK) channels in POMC neurons and GABAB receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24h following steroid administration in vivo, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α 1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.",
keywords = "Dopamine, GABA, K channel, Norepinephrine, POMC, Protein kinase",
author = "Martin Kelly and Jian Qiu and Wagner, {Edward J.} and Oline Ronnekleiv",
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TY - JOUR

T1 - Rapid effects of estrogen on G protein-coupled receptor activation of potassium channels in the central nervous system (CNS)

AU - Kelly, Martin

AU - Qiu, Jian

AU - Wagner, Edward J.

AU - Ronnekleiv, Oline

PY - 2002/12

Y1 - 2002/12

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. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca2+-activated K+ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K + (GIRK) channels in POMC neurons and GABAB receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24h following steroid administration in vivo, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α 1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.

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. Some of the neurons include neurosecretory neurons such as gonadotropin-releasing hormone (GnRH) and dopamine neurons, and local circuitry neurons such as proopiomelanocortin (POMC) and γ-aminobutyric acid (GABA) neurons. We have elucidated several non-genomic pathways through which the steroid alters synaptic responses in these hypothalamic neurons. We have examined the modulation by estrogen of the coupling of various receptor systems to inwardly-rectifying and small-conductance, Ca2+-activated K+ (SK) channels using intracellular sharp-electrode and whole-cell recording techniques in hypothalamic slices from ovariectomized female guinea pigs. Estrogen rapidly uncouples μ-opioid receptors from G protein-gated inwardly-rectifying K + (GIRK) channels in POMC neurons and GABAB receptors from GIRK channels in dopamine neurons as manifested by a reduction in the potency of μ-opioid and GABAB receptor agonists to hyperpolarize their respective cells. This effect is blocked by inhibitors of protein kinase A (PKA) and protein kinase C (PKC). In addition, after 24h following steroid administration in vivo, the GABAB/GIRK channel uncoupling observed in GABAergic neurons of the preoptic area is associated with reduced agonist efficacy. Conversely, estrogen enhances the efficacy of α 1-adrenergic receptor agonists to inhibit apamin-sensitive SK currents in these preoptic GABAergic neurons, and does so in both a rapid and sustained fashion. Finally, we observed a direct, steroid-induced hyperpolarization of GnRH neurons. These findings indicate a richly complex yet coordinated steroid modulation of K+ channel activity in hypothalamic (POMC, dopamine, GABA, GnRH) neurons that are involved in regulating numerous homeostatic functions.

KW - Dopamine

KW - GABA

KW - K channel

KW - Norepinephrine

KW - POMC

KW - Protein kinase

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