MOLECULAR AND FUNCTIONAL BASIS ODORANT RECOGNITION

分子和功能基础的气味识别

• 批准号: 6516260
• 负责人: RANDALL R REED
• 金额: $ 16.35万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6516260
• 关键词: aldehydes; anosmia; behavior test; behavioral /social science research tag; chemoreceptors; genetic models; genetically modified animals; genome; laboratory mouse; neurons; odors; olfactions; polymerase chain reaction; receptor binding; receptor expression; receptor sensitivity; sensory discrimination; single cell analysis; tissue /cell culture

The mammalian olfactory system displays remarkable sensitivity and specificity in the detection of odorant molecules. G protein-coupled receptors present in the cilia of the olfactory neurons activate a transduction cascade leading to electrical activity and the propagation of sensory information to the brain. The discovery of a large family of olfactory receptor (OR) genes nearly a decade ago provided an explanation for the differential sensitivity of individual olfactory neurons. Moreover, the apparent expression of only a single receptor type in each cell suggests that the selectivity and specificity characteristic of each neuron reflects the functional properties of the underlying receptor protein. However, until recently it had not been possible to characterize OR function by expression in heterologous systems. Preliminary analysis of a few receptors indicates that they may display relatively narrow ligand specificity. The development of functional expression systems presents an important opportunity to define the molecular mechanism underlying odorant recognition. Interestingly, the threshold for detection of some odorants differs greatly among individuals in the population. These specific anosmias and hyposmias appear to have a genetic basis and may derive from unappreciated variations in the complement and functionality of individual receptors. We propose to define the molecular logic used by odorant receptors to bind and discriminate among structurally related ligands. These experiments will characterize the ligand specificity of a large number of mouse olfactory receptors and probe key residues in the ligand recognition pocket. The evolution and structural conservation of olfactory receptors make them uniquely amenable to a systematic dissection of molecular recognition. We will utilize molecular and functional approaches to elucidate the genetic and genomic variations that lead to specific anosmias. These experiments will complement those derived from in vitro analysis by providing information on receptor genes that are functionally important in the behavioral response of an animal. These experiments will afford new insights into the basis of odorant discrimination, information coding and the genetic basis of variation in sensory perception by the mammalian brain.

哺乳动物嗅觉系统在检测气味分子时表现出显着的灵敏度和特异性。 嗅觉神经元纤毛中存在的G蛋白偶联受体激活转导级联反应，从而导致电活动和感官信息传播给大脑。大约十年前发现了大型嗅觉受体（OR）基因的大家庭为单个嗅觉神经元的差异敏感性提供了解释。 此外，每个细胞中仅单个受体类型的明显表达表明，每个神经元的选择性和特异性特征反映了基础受体蛋白的功能特性。 但是，直到最近，还不能通过在异源系统中的表达来表征或功能。 对一些受体的初步分析表明它们可能表现出相对狭窄的配体特异性。 功能表达系统的开发为定义有气味识别的分子机制提供了重要的机会。 有趣的是，在人群中，检测某些气味的阈值在很大程度上有很大不同。 这些特定的厌氧和低血压似乎具有遗传基础，并且可能源于单个受体的补体和功能的不贴切的变化。我们建议定义气味受体用来结合和区分结构相关的配体的分子逻辑。 这些实验将表征大量小鼠嗅觉受体和配体识别袋中探针键残基的配体特异性。 嗅觉受体的进化和结构保守使它们与系统识别的系统解剖有关。我们将利用分子和功能方法来阐明导致特定厌氧的遗传和基因组变异。 这些实验将通过提供有关动物行为反应在功能上重要的受体基因的信息来补充从体外分析中得出的实验。这些实验将提供有关气味歧视，信息编码和哺乳动物大脑感觉感知变化的遗传基础的新见解。