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: 8361423
• 负责人: Timothy Holy
• 金额: $ 2.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-01-01 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361423
• 关键词: Afferent Neurons; Animals; Charge; Chemical Structure; Chemicals; Collection; Communication; Corticosterone; Cues; Female; Funding; Glucocorticoids; Grant; Hydrophobicity; Individual; Inorganic Sulfates; Ligands; Mass Spectrum Analysis; Measures; Molecular; Molecular Weight; Mus; National Center for Research Resources; Nature; Neurons; Odors; Pheromone; Physiological; Principal Investigator; Property; Reporting; Research; Research Infrastructure; Resources; Sensory; Signal Transduction; Social status; Source; Stimulus; Stress; Sulfatases; United States National Institutes of Health; Unspecified or Sulfate Ion Sulfates; Urine; Variant; biomedical resource; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 在小鼠中，信息素和其他社会气味线索传达有关性别、社会地位和身份的信息；然而，这些线索的分子性质基本上是未知的。为了识别这些线索，我们使用多电极阵列（MEA）记录筛选了雌性小鼠尿液的色谱部分，以确定它们是否能够导致信息素检测犁鼻感觉神经元（VSN）中可重复的放电率增加。发现活性化合物的基本性质非常均匀，大多数具有低分子量、中等疏水性、低挥发性并具有负电荷。活性化合物的纯化和结构分析揭示了多种硫酸化类固醇，其中两种被鉴定为硫酸化糖皮质激素，包括21-硫酸皮质酮。硫酸酯酶处理的尿液提取物失去了超过 80% 的活性，表明硫酸化化合物是雌性小鼠尿液中主要的 VSN 配体。根据 MEA 记录测量，31 种合成硫酸化类固醇的集合触发反应的频率比包含大多数先前报道的所有 VSN 配体的类似大小的刺激组高 30 倍。总的来说，VSN 检测到了所有主要类别的硫酸化类固醇，但单个神经元对化学结构的微小变化很敏感。雄性和雌性的 VSN 均检测到了硫酸类固醇，但感觉转导通道 TRPC2 的敲除并未检测到这些化合物。在应激动物中，两种硫酸化糖皮质激素的尿液浓度增加了许多倍，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。这些结果为小鼠之间的化学通讯信号提供了前所未有的表征。