MOLECULAR AND FUNCTIONAL BASIS ODORANT RECOGNITION

哺乳动物的嗅觉系统在检测气味分子方面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蛋白偶联受体激活了一系列转导通路，导致电活动和感觉信息向大脑的传播。近十年前，一个嗅觉受体(OR)基因大家族的发现为个体嗅觉神经元的差异敏感性提供了解释。此外，每个细胞中只有一种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潜在受体蛋白的功能特性。然而，直到最近，还不可能通过在异源系统中的表达来表征OR功能。对一些受体的初步分析表明，它们可能表现出相对较窄的配基特异性。功能表达系统的发展为确定气味识别的分子机制提供了一个重要的机会。有趣的是，一些气味的检测阈值在种群中的不同个体之间差别很大。这些特殊的嗅觉障碍和先天性畸形似乎有遗传基础，可能源于个体受体的补体和功能上的意外变异。我们建议定义气味受体用于结合和区分结构上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的配基特异性，并探索配基识别口袋中的关键残基。嗅觉感受器的进化和结构保守使它们独特地服从于对分子识别的系统剖析。我们将利用分子和功能方法来阐明导致特定嗅觉缺失的遗传和基因组变异。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。这些实验将为哺乳动物大脑辨别气味的基础、信息编码和感觉变化的遗传基础提供新的见解。

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.