SULFATED STEROIDS AS NATURAL LIGANDS OF MOUSE PHEROMONE-SENSING NEURONS

硫酸类固醇作为小鼠信息素感知神经元的天然配体

• 批准号: 8168833
• 负责人: Timothy Holy
• 金额: $ 0.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-10 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168833
• 关键词: Afferent Neurons; Animals; Charge; Chemical Structure; Chemicals; Collection; Communication; Computer Retrieval of Information on Scientific Projects Database; Corticosterone; Cues; Female; Funding; Glucocorticoids; Grant; Hydrophobicity; Individual; Inorganic Sulfates; Institution; Ligands; Measures; Molecular; Molecular Weight; Mus; Nature; Neurons; Odors; Pheromone; Physiological; Property; Reporting; Research; Research Personnel; Resources; Sensory; Signal Transduction; Social status; Source; Stimulus; Stress; Sulfatases; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Urine; Variant; male; response; sex; social; steroid sulfate

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Among mice, pheromones and other social odor cues convey information about sex, social status, and identity; however, the molecular nature of these cues is essentially unknown. To identify these cues, we screened chromatographic fractions of female mouse urine for their ability to cause reproducible firing rate increases in the pheromone-detecting vomeronasal sensory neurons (VSNs) using multielectrode array (MEA) recording. Active compounds were found to be remarkably homogenous in their basic properties, with most being of low molecular weight, moderate hydrophobicity, low volatility, and possessing a negative electric charge. Purification and structural analysis of active compounds revealed multiple sulfated steroids, of which two were identified as sulfated glucocorticoids, including corticosterone 21-sulfate. Sulfatase-treated urine extracts lost >80% of their activity, indicating that sulfated compounds are the predominant VSN ligands in female mouse urine. As measured by MEA recording, a collection of 31 synthetic sulfated steroids triggered responses 30-fold more frequently than did a similarly sized stimulus set containing the majority of all previously reported VSN ligands. Collectively, VSNs detected all major classes of sulfated steroids, but individual neurons were sensitive to small variations in chemical structure. VSNs from both males and females detected sulfated steroids, but knock-outs for the sensory transduction channel TRPC2 did not detect these compounds. Urine concentrations of the two sulfated glucocorticoids increased many fold in stressed animals, indicating that information about physiological status is encoded by the urine concentration of particular sulfated steroids. These results provide an unprecedented characterization of the signals available for chemical communication among mice.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在小鼠中，信息素和其他社会气味提示传达了有关性，社会地位和身份的信息；但是，这些提示的分子性质本质上是未知的。为了识别这些提示，我们筛选了雌性小鼠尿液的色谱分数，以便使用多电极阵列（MEA）记录在信息素检测到的vomeronasal感觉神经元（VSNS）中引起可重复发射速率的能力增加。发现活性化合物的基本特性非常均匀，其中大多数具有低分子量，中等疏水性，低挥发性和负电荷。活性化合物的纯化和结构分析显示多种硫酸化类固醇，其中两种被鉴定为硫酸化的糖皮质激素，包括皮质酮21-硫酸盐。硫酸酶处理的尿液提取物损失了其活性的80％，表明硫化化合物是雌性小鼠尿液中主要的VSN配体。通过MEA记录衡量，比相似大小的刺激组集合的31次合成硫酸化类固醇的集合触发了30倍的反应，这些刺激集包含所有先前报道的VSN配体中的大多数。总体而言，VSN检测到了所有主要类硫化类固醇，但单个神经元对化学结构的较小变化敏感。来自男性和女性的VSN都检测到硫酸化的类固醇，但是感觉转导通道TRPC2的敲除未检测到这些化合物。两种硫酸化的糖皮质激素的尿液浓度增加了压力动物的许多折叠，表明有关生理状态的信息是由特定硫酸化类固醇的尿液浓度编码的。这些结果提供了用于小鼠化学通信的信号的前所未有的表征。