The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic γ-aminobutyric acid neurons: Pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis

Edward J. Wagner, Oline Ronnekleiv, Martin Kelly

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Abstract

The present study sought to determine whether small-conductance, Ca2+-activated K+ currents underlie the afterhyperpolarization (AHP) in neurons of the preoptic area (POA), a brain region important in controlling reproduction. We used an ovariectomized, female guinea pig model to test two hypotheses: 1) the current associated with the AHP (IAHP) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal steroid-sensitive manner. Intracellular recordings followed by combined histofluorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa isomer, revealed that POA neurons, including γ-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding IAHP was sensitive to antagonism by CdCl2 (200 μM), apamin (0.3-1 μM), and dequalinium (3 μM). The β-adrenergic receptor agonist isoproterenol inhibited the IAHP in a dose-dependent, timolol-sensitive fashion. In addition, the α1-adrenergic receptor agonist methoxamine dose dependently inhibited the IAHP in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 μg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the IAHP, whereas that for isoproterenol was unaffected. Similarly, bath application of 17β-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the IAHP. Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the IAHP, and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the α1-adrenergic receptor-mediated inhibition of this current.

Original languageEnglish (US)
Pages (from-to)21-30
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume299
Issue number1
StatePublished - 2001

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Apamin
Aminobutyrates
Calcium-Activated Potassium Channels
Preoptic Area
Methoxamine
Estrogens
Pharmacology
Neurons
GABAergic Neurons
Adrenergic Agonists
Isoproterenol
Dequalinium
Cadmium Chloride
Timolol
Glutamate Decarboxylase
Prazosin
Baths
Adrenergic Receptors
Amines
In Situ Hybridization

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic γ-aminobutyric acid neurons: Pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis",
abstract = "The present study sought to determine whether small-conductance, Ca2+-activated K+ currents underlie the afterhyperpolarization (AHP) in neurons of the preoptic area (POA), a brain region important in controlling reproduction. We used an ovariectomized, female guinea pig model to test two hypotheses: 1) the current associated with the AHP (IAHP) regulates the firing rate of POA neurons and 2) amine neurotransmitters modulate it in a gonadal steroid-sensitive manner. Intracellular recordings followed by combined histofluorescence/in situ hybridization for glutamic acid decarboxylase, 65-kDa isomer, revealed that POA neurons, including γ-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding IAHP was sensitive to antagonism by CdCl2 (200 μM), apamin (0.3-1 μM), and dequalinium (3 μM). The β-adrenergic receptor agonist isoproterenol inhibited the IAHP in a dose-dependent, timolol-sensitive fashion. In addition, the α1-adrenergic receptor agonist methoxamine dose dependently inhibited the IAHP in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 μg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the IAHP, whereas that for isoproterenol was unaffected. Similarly, bath application of 17β-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the IAHP. Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the IAHP, and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the α1-adrenergic receptor-mediated inhibition of this current.",
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T1 - The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic γ-aminobutyric acid neurons

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AU - Ronnekleiv, Oline

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