Progesterone-metabolite prevents protein kinase C-dependent modulation of γ-aminobutyric acid type A receptors in oxytocin neurons
Progesterone-metabolite prevents protein kinase C-dependent modulation of γ-aminobutyric acid type A receptors in oxytocin neurons
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DOI：
10.1073/pnas.050424697
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发表时间：
2000-03-28
影响因子：
11.1
通讯作者：
Kits, KS
中科院分区：
文献类型：
--
作者：
Brussaard, AB;Wossink, J;Kits, KS
孕期性腺类固醇对催产素神经元的反馈部分是通过神经类固醇别孕酮(3α-OH-DHP)作为突触后γ-氨基丁酸(GABA(A))受体的变构调节剂来实现的。在这里，我们描述了一种非基因组孕酮信号的形式，表明3α-OH-DHP不仅增强了GABA(A)受体通道的活性，而且还阻止了蛋白激酶C(PKC)对其进行调节。应用催产素或刺激PKC可抑制催产素神经元突触后的GABA反应，但不能抑制3α-OH-DHP的存在。这一发现在幼年期和妊娠晚期是正确的，当时GABA(A)受体对3α-OH-DHP敏感。相反，在分娩后，当催产素神经元表达的GABA(A)受体对3α-OH-DHP不那么敏感时，这种神经类固醇不再抵消PKC。GABA(A)受体对3α-OH-DHP反应性的改变有助于解释分娩时放电活动的开始，从而诱导催产素的释放。
Gonadal steroid feedback to oxytocin neurons during pregnancy is in part mediated via the neurosteroid allopregnanolone (3 alpha-OH-DHP), acting as allosteric modulator of postsynaptic gamma-aminobutyric acid type A (GABA(A)) receptors. We describe here a form of nongenomic progesterone signaling by showing that 3 alpha-OH-DHP not only potentiates GABA(A) receptor-channel activity but also prevents its modulation by protein kinase C (PKC). Application of oxytocin or stimulation of PKC suppressed the postsynaptic GABA responses of oxytocin neurons in the absence, but not in the presence of 3 alpha-OH-DHP. This finding was true at the juvenile stage and during late pregnancy, when the GABA(A) receptor is sensitive to 3 alpha-OH-DHP. In contrast, after parturition, when the GABA(A) receptors expressed by oxytocin neurons are less sensitive to 3 alpha-OH-DHP, this neurosteroid no longer counteracts PKC. The change in GABA(A)-receptor responsiveness to 3 alpha-OH-DHP helps to explain the onset of firing activity and thus the induction of oxytocin release at parturition.