Charlier Thierry D, Cornil Charlotte A, Ball Gregory F, Balthazart Jacques
GIGA Neurosciences, University of Liège, 4000 Liège, Belgium.
Biochim Biophys Acta. 2010 Oct;1800(10):1094-105. doi: 10.1016/j.bbagen.2009.12.010. Epub 2010 Jan 12.
The mechanisms through which estrogens modulate neuronal physiology, brain morphology, and behavior in recent years have proven to be far more complex than previously thought. For example, a second nuclear estrogen receptor has been identified, a new family of coregulatory proteins regulating steroid-dependent gene transcriptions was discovered and, finally, it has become clear that estrogens have surprisingly rapid effects based on their actions on cell membranes, which in turn result in the modulation of intracellular signaling cascades.
This paper presents a selective review of new findings in this area related to work in our laboratories, focusing on the role of estrogens in the activation of male sexual behavior. Two separate topics are considered. We first discuss functions of the steroid receptor coactivator-1 (SRC-1) that has emerged as a key limiting factor for behavioral effects of estradiol. Knocking-down its expression by antisense oligonucleotides drastically inhibits male-typical sexual behaviors. Secondly, we describe rapid regulations of brain estradiol production by calcium-dependent phosphorylations of the aromatase enzyme, themselves under the control of neurotransmitter activity.
These rapid changes in estrogen bioavailability have clear behavioral consequences. Increases or decreases in estradiol concentrations respectively obtained by an acute injection of estradiol itself or of an aromatase inhibitor lead within 15-30 min to parallel changes in sexual behavior frequencies.
These new controls of estrogen action offer a vast array of possibilities for discrete local controls of estrogen action. They also represent a formidable challenge for neuroendocrinologists trying to obtain an integrated view of brain function in relation to behavior.
近年来，雌激素调节神经元生理、脑形态和行为的机制已被证明远比先前认为的复杂得多。例如，已鉴定出第二种核雌激素受体，发现了一个调节类固醇依赖性基因转录的新的共调节蛋白家族，最后，很明显雌激素基于其对细胞膜的作用具有惊人的快速效应，进而导致细胞内信号级联反应的调节。
本文对该领域与我们实验室工作相关的新发现进行了选择性综述，重点关注雌激素在激活雄性性行为中的作用。考虑了两个不同的主题。我们首先讨论类固醇受体共激活因子-1（SRC-1）的功能，它已成为雌二醇行为效应的关键限制因素。用反义寡核苷酸敲低其表达会大幅抑制雄性典型性行为。其次，我们描述了芳香化酶的钙依赖性磷酸化对脑内雌二醇产生的快速调节，而芳香化酶本身受神经递质活性的控制。
雌激素生物利用度的这些快速变化具有明显的行为后果。通过急性注射雌二醇本身或芳香化酶抑制剂分别获得的雌二醇浓度升高或降低，会在15 - 30分钟内导致性行为频率的平行变化。
雌激素作用的这些新调控为雌激素作用的离散局部调控提供了大量可能性。它们也对试图获得与行为相关的脑功能综合观点的神经内分泌学家构成了巨大挑战。
