Role of Palmitolyation on Neuronal Estrogen and Androgen Receptor Function

雌激素受体最初被描述为细胞内受体，仅在调节生殖行为的大脑区域起作用。最近的研究发现，整个神经系统的各种神经元通过激活表面膜受体对雌二醇产生反应。现在已知这些膜雌激素受体会导致学习和记忆、性感受性、运动控制和疼痛的改变。在这方面，神经系统并不是唯一的，因为膜雌激素受体影响生殖器官、心血管系统和骨骼。这个项目的目标是确定雌激素受体是如何适应作为表面膜信号分子。该项目将测试雌激素受体的棕榈酰化是将细胞内受体转化为膜信号蛋白的重要调节步骤的假设。已知有23种不同的酶可以使蛋白质棕榈酰化。主要目标是确定23种酶中的哪一种负责雌激素受体棕榈酰化，然后确定操纵脑内雌激素受体棕榈酰化的生理和行为影响。确定蛋白质的棕榈酰化类固醇受体提供了一个创新的实验系统，将挑战教条和培训人员整合各种体内和体外模型系统。最先进的细胞/分子方法将与已建立的行为方法相结合。使用特定的评估工具，Mermelstein博士将监测他的学员的技术，智力和教学发展。Mermelstein博士和他的学生还将参加多个外展活动，包括开发神经科学未成年人作为明尼苏达大学本科课程的一部分。

Estrogen receptors were originally characterized as intracellular receptors, acting only in brain regions that regulate reproductive behaviors. Recent discoveries have identified that various neurons throughout the nervous system exhibit responses to estradiol through the activation of surface membrane receptors. These membrane estrogen receptors are now known to lead to alterations in learning and memory, sexual receptivity, motor control and pain. The nervous system is not unique in this regard, as membrane estrogen receptors affect the reproductive organs, the cardiovascular system and bone. The goal of this project is to determine how estrogen receptors are adapted to act as surface membrane signaling molecules. The project willl test the hypothesis that palmitoylation of the estrogen receptor is the essential regulatory step in converting intracellular receptors into membrane signaling proteins. There are 23 different enzymes known to palmitoylate proteins. The principal goal is to identify which of the 23 enzymes is responsible for estrogen receptor palmitoylation, and then to determine the physiological and behavioral impact of manipulating estrogen receptor palmitoylation within brain. Identifying the proteins that palmitoylate steroid receptors provides an innovative experimental system that will challenge dogma and train personnel to integrate various in vivo and in vitro model systems. State-of-the-art cellular/molecular methods will be integrated with established behavioral approaches. Using specific assessment tools, Dr. Mermelstein will monitor the technical, intellectual and instructional development of his trainees. Dr. Mermelstein and his students will also participate in multiple outreach activities, including the development of a Neuroscience Minor as part of the undergraduate curriculum at the University of Minnesota.