Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype.
Differential regulation of gonadotropin-releasing hormone neuron activity and membrane properties by acutely applied estradiol: dependence on dose and estrogen receptor subtype.
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DOI：
10.1523/jneurosci.0352-09.2009
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发表时间：
2009-04-29
期刊：
影响因子：
--
通讯作者：
Moenter SM
中科院分区：
文献类型：
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作者：
Chu Z;Andrade J;Shupnik MA;Moenter SM
GnRH神经元对控制生育能力至关重要。在体内，雌二醇可根据浓度和生理状态抑制或刺激GnRH的释放。我们研究了雌二醇的快速非基因组效应。全细胞记录的GnRH神经元从卵巢切除小鼠脑切片，离子性GABA和谷氨酸受体阻断。用雌二醇泡浴并在15分钟内完成测量。雌二醇从高生理（排卵前）浓度（100pM）到100nM增强动作电位放电，降低后超极化电位（AHP）和增加慢后去极化（sADP）振幅，降低IAHP和增强IADP。IAHP的降低被先前钙活化钾通道的阻断所阻断。这些作用被雌激素受体(ER) β特异性激动剂模拟，并被经典受体拮抗剂ICI182780阻断。ERα或GPR30激动剂没有影响。高生理性雌二醇对放电速率的急性刺激作用依赖于通过蛋白激酶a的信号传导。相反，低生理性雌二醇水平（10pM）不影响内在特性。然而，在不阻断嗜离子性GABA和谷氨酸受体的情况下，10pM雌二醇减少了GnRH神经元的放电；这被ERα激动剂模仿。ERα激动剂降低GABA向GnRH神经元传递的频率；GABA可以激发这些细胞。相反，ERβ激动剂增加GABA传递和突触后反应。这些数据表明，雌二醇对GnRH神经元的快速内在和网络调节取决于剂量和受体亚型。在基因组作用的配合下，非基因组效应可能在GnRH分泌的反馈调节中发挥作用。
GnRH neurons are critical to controlling fertility. In vivo, estradiol can inhibit or stimulate GnRH release depending on concentration and physiological state. We examined rapid, non-genomic effects of estradiol. Whole-cell recordings were made of GnRH neurons in brain slices from ovariectomized mice with ionotropic GABA and glutamate receptors blocked. Estradiol was bath-applied and measurements completed within 15 min. Estradiol from high physiological (preovulatory) concentrations (100pM) to 100nM enhanced action potential firing, reduced afterhyperpolarizing potential (AHP) and increased slow afterdepolarization (sADP) amplitudes, and reduced IAHP and enhanced IADP. The reduction of IAHP was occluded by prior blockade of calcium-activated potassium channels. These effects were mimicked by an estrogen receptor (ER) β-specific agonist and were blocked by the classical receptor antagonist ICI182780. ERα or GPR30 agonists had no effect. The acute stimulatory effect of high physiological estradiol on firing rate was dependent on signaling via protein kinase A. In contrast, low physiological levels of estradiol (10pM) did not affect intrinsic properties. Without blockade of ionotropic GABA and glutamate receptors, however, 10pM estradiol reduced firing of GnRH neurons; this was mimicked by an ERα agonist. ERα agonists reduced the frequency of GABA transmission to GnRH neurons; GABA can excite to these cells. In contrast, ERβ agonists increased GABA transmission and postsynaptic response. These data suggest rapid intrinsic and network modulation of GnRH neurons by estradiol is dependent upon both dose and receptor subtype. In cooperation with genomic actions, non-genomic effects may play a role in feedback regulation of GnRH secretion.