Rapid Signaling Pathway for Corticosteriods

IBN-9604200兰花类固醇激素是已知的对大脑功能和行为最有效的调节剂之一。因此，了解类固醇的作用机制是神经内分泌学和行为神经科学的一个基本问题。直到最近，类固醇被认为是通过两个步骤起作用的。类固醇，如雌二醇、睾酮和皮质酮，首先进入大脑，并与目标神经元中发现的特定受体结合。类固醇受体复合体随后被激活并与DNA结合，DNA反过来调节基因表达并改变蛋白质合成。正是蛋白质的增加或减少导致了对类固醇激素的生理和行为反应。这被称为类固醇作用的基因组机制，作用的时间范围从几个小时到几天不等。由于类固醇的许多神经活动出现并迅速减少，因此存在一个概念性问题。这对皮质酮尤其如此，皮质酮是一种在压力下释放的肾上腺类固醇。事实上，众所周知，在压力条件下，皮质类固醇水平在2-5分钟内急剧上升，在30分钟内达到峰值，并随着压力事件的停止而几乎同样迅速地恢复到基础水平。Orchinik博士认为，在急性应激条件下，皮质类固醇是通过非基因组机制发挥作用的，该奖项解决了这一重要问题。他假设，皮质类固醇首先与神经细胞膜上的受体结合，而不是神经元内，从而引发快速的神经元反应。奥奇尼克博士将开展一系列研究，系统地研究皮质类固醇对神经生理和行为反应的分子机制，这些反应太快，无法用基因组作用机制来解释。初步研究将建立和表征神经细胞膜中皮质酮受体的存在。然后将对膜结合和细胞内皮质类固醇脑受体进行比较。然后，奥奇尼克博士将使用一系列技术，研究皮质酮与膜受体结合后发生的事件。他将确定膜结合类固醇启动的信号转导是否涉及与GTP结合蛋白的受体相互作用，类似于神经递质的作用。这些研究的结果将确定参与皮质类固醇快速作用的生化途径。从这些研究中获得的新知识将帮助我们破译类固醇作用的基因组和非基因组机制，如果我们要了解激素如何调节大脑功能和行为，特别是神经对应激的反应，这是必不可少的。

IBN-9604200 Orchinik Steroid hormones are among the most powerful regulators of brain function and behavior known. For this reason, understanding the mechanism for steroid actions is a fundamental problem for neuroendocrinology and behavioral neuroscience. Until recently, steroids were thought to act through a two-step process. Steroids, such as estradiol, testosterone, and corticosterone, first enter the brain and bind to specific receptors found within target neurons. The steroid-receptor complex is then activated and binds to DNA, which in turn, regulates gene expression and alters protein synthesis. It is the increase or decrease of proteins that bring about the physiological and behavioral response to the steroid hormones. This is referred to as the genomic mechanism of steroid action and the time frame of action requires anywhere from hours to days. A conceptual problem exists since many neural actions of steroid appear and decrement very rapidly. This is especially true for corticosterone, an adrenal steroid, that is released during stress. Indeed, it has been known for years that under stressful conditions, corticosteroids levels rise dramatically within 2-5 minutes, peak within 30 minutes, and return to basal levels almost as quickly with the cessation of the stressful event. Dr. Orchinik believes that under acute stress conditions, corticosteroid is acting through a non-genomic mechanism and this award addresses this important question. He hypothesizes that corticosteroids are eliciting rapid neuronal responses by first binding to receptors in the neuronal membranes rather than within the neuron. Dr. Orchinik will carry out a series of studies that systematically investigate the molecular mechanisms that underlie neurophysiological and behavioral responses to corticosteroid that are too rapid to be accounted for by the genomic mechanism of action. Initial studies will establish and characterized the presence of corticosterone r eceptors in neuronal membranes. The membrane-bound and intracellular corticosteroid brain receptors will then be compared. Using an array of techniques, Dr. Orchinik will then examine the events that occur after corticosterone binds to the membrane receptors. He will determine whether the signal transduction initiated by the membrane-bound steroid involved receptor interactions with GTP binding proteins, similar to the action of neurotransmitters. The results from these studies will identify the biochemical pathways involved in the rapid corticosteroid action. The new knowledge gained from these studies will help us decipher both the genomic and non-genomic mechanisms of steroid action which is essential if we are to understand of how hormones modulate brain function and behavior, in particular, neural responses to stress.