The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis.
The noradrenergic inhibition of an apamin-sensitive, small-conductance Ca2+-activated K+ channel in hypothalamic gamma-aminobutyric acid neurons: pharmacology, estrogen sensitivity, and relevance to the control of the reproductive axis.
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发表时间：
2001-10
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通讯作者：
Edward J. Wagner;O. Rønnekleiv;M. Kelly
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作者：
Edward J. Wagner;O. Rønnekleiv;M. Kelly
本研究旨在确定小电导，Ca2+激活的K+电流是否在视前区（POA）神经元的后超极化（AHP）基础上，POA是控制生殖的重要大脑区域。我们使用切除卵巢的雌性豚鼠模型来验证两个假设：1)与AHP相关的电流（I(AHP)）调节POA神经元的放电速率；2)胺类神经递质以性腺类固醇敏感的方式调节它。细胞内记录和65 kda异构体谷氨酸脱羧酶的组织荧光/原位杂交显示，包括γ -氨基丁酸（GABA）能神经元在内的POA神经元表现出AHP和峰值频率适应。相应的I（AHP）对CdCl2 （200 μ m）、apamin （0.3-1 μ m）和dequalinium （3 μ m）的拮抗作用敏感。肾上腺素能受体激动剂异丙肾上腺素抑制I（AHP）呈剂量依赖性，对噻莫洛尔敏感。此外，α -肾上腺素能受体激动剂甲氧沙明剂量依赖性地抑制I(AHP)，并以吡嗪敏感的方式增加神经元放电率。苯甲酸雌二醇（estradiol benzoate， EB; 25 μ g, s.c）预处理24小时可显著增强甲氧胺对I（AHP）的抑制作用，而对异丙肾上腺素的抑制作用不受影响。同样，17 - β -雌二醇（100 nM; 15-20 min）浴用模拟EB对甲氧胺诱导的I（AHP）抑制的影响。因此，POA gabaergy神经元表达一种阿帕胺敏感通道，该通道至少部分介导I(AHP)，并调节这些细胞的兴奋性。此外，这些研究表明，雌激素增强了α 1-肾上腺素能受体介导的这种电流的抑制。
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 (I(AHP)) 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 gamma-aminobutyric acid (GABA)ergic neurons, exhibited an AHP and spike frequency adaptation. The corresponding I(AHP) was sensitive to antagonism by CdCl2 (200 microM), apamin (0.3-1 microM), and dequalinium (3 microM). The beta-adrenergic receptor agonist isoproterenol inhibited the I(AHP) in a dose-dependent, timolol-sensitive fashion. In addition, the alpha1-adrenergic receptor agonist methoxamine dose dependently inhibited the I(AHP) in a prazosin-sensitive manner and increased neuronal firing rate. Twenty-four-hour pretreatment with estradiol benzoate (EB; 25 microg, s.c.) markedly potentiated the inhibitory effect of methoxamine on the I(AHP), whereas that for isoproterenol was unaffected. Similarly, bath application of 17beta-estradiol (100 nM; 15-20 min) mimicked the effect of EB on the methoxamine-induced inhibition of the I(AHP). Thus, POA GABAergic neurons express an apamin-sensitive channel that mediates, at least in part, the I(AHP), and tempers the excitability of these cells. Furthermore, these studies demonstrate that estrogen enhances the alpha1-adrenergic receptor-mediated inhibition of this current.