MOLECULAR AND FUNCTIONAL BASIS ODORANT RECOGNITION

哺乳动物的嗅觉系统在气味分子的检测中表现出显著的敏感性和特异性。 存在于嗅觉神经元纤毛中的G蛋白偶联受体激活导致电活动和将感觉信息传播到大脑的转导级联。近十年前，嗅觉受体（OR）基因大家族的发现为单个嗅觉神经元的差异敏感性提供了解释。 此外，在每个细胞中仅单一受体类型的表观表达表明每个神经元的选择性和特异性特征反映了潜在受体蛋白的功能特性。 然而，直到最近，它还没有能够表征或功能的表达在异源系统。 一些受体的初步分析表明，它们可能显示相对狭窄的配体特异性。 功能表达系统的发展为确定气味识别的分子机制提供了重要的机会。 有趣的是，检测某些气味的阈值在人群中的个体之间差异很大。 这些特异性的嗅觉缺失和嗅觉减退似乎有遗传基础，可能来源于个体受体的补体和功能的未被认识到的变异。我们建议定义的气味受体结合和结构相关的配体之间的歧视所使用的分子逻辑。 这些实验将表征大量小鼠嗅觉受体的配体特异性，并探测配体识别口袋中的关键残基。 嗅觉受体的进化和结构保守性使它们特别适合于分子识别的系统解剖。我们将利用分子和功能的方法来阐明遗传和基因组变异，导致特定的anosystem。 这些实验将通过提供在动物行为反应中具有重要功能的受体基因的信息来补充那些来自体外分析的实验。这些实验将提供新的见解的基础上气味的歧视，信息编码和遗传基础上的变化，在感官知觉的哺乳动物大脑。

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.