CELLULAR AND MOLECULAR MECHANISMS OF OLFACTORY CODING

嗅觉编码的细胞和分子机制

• 批准号: 6636794
• 负责人: JOHN J. NGAI
• 金额: $ 33.71万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6636794
• 关键词: G protein coupled receptor kinase; Xenopus oocyte; affinity chromatography; cell line; chemoreceptors; goldfish; immunocytochemistry; laboratory mouse; laboratory rabbit; limbic system; neural information processing; odors; olfactions; olfactory stimulus; protein structure function; sensory discrimination; site directed mutagenesis; western blottings; zebrafish

DESCRIPTION (provided by applicant): Vertebrates can recognize and discriminate thousands of odorants of diverse molecular structure. How is this process of molecular recognition accomplished? The identification of an odorant's chemical structure is thought to occur through the combinatorial integration from multiple odorant receptors, each tuned to recognize different molecular features. Thus, by elucidating the molecular specificities of the odorant receptors we will gain a better understanding how information is processed in the olfactory system. In this application, we focus on the properties of the "C family" G protein-coupled receptors expressed in the vertebrate olfactory system. This receptor family includes the putative pheromone-sensing receptors of the mammalian vomeronasal system and the amino acid sensing receptor of the fish olfactory system. Our studies comprise three lines of investigation: (1) Based on the known structure of related receptors, we will perform molecular modeling and functional validation on the ligand binding pocket of a goldfish odorant receptor activated by amino acids - potent odorants for fish. Through this approach, we will identify the critical interactions between ligand and receptor that afford molecular specificity and lead to odorant receptor activation. (2) To unravel the receptor combinatorials used to encode olfactory information, we will isolate additional C family olfactory receptors from the goldfish and zebrafish and identify their cognate ligands. By characterizing the molecular specificities of a broader collection of odorant receptors, we will understand with greater clarity how multiple receptors are used in combination to recognize and discriminate odorants. (3) Recent evidence suggests that some odorant receptors can be coexpressed within the same sensory neuron. Do multiple receptors function independently within a cell, or do they form heteromeric complexes whose ligand specificities are an emerging property of the intermolecular interaction? We will determine whether members of the C family olfactory receptors form oligomeric complexes and whether aspects of receptor function - including ligand specificity, signal transduction, and intracellular trafficking - are altered in hetero-oligomeric complexes. These studies will help establish what role, if any, receptor oligomerization plays in determining and diversifying the response specificity of the olfactory sensory neuron. Together our studies will help to elucidate the molecular and cellular mechanisms of olfactory coding.

描述（由申请人提供）：脊椎动物可以识别和区分数千种不同分子结构的气味剂。这个分子识别过程是如何完成的？人们认为，气味剂化学结构的识别是通过多个气味剂受体的组合整合来实现的，每个受体都经过调整以识别不同的分子特征。因此，通过阐明气味受体的分子特异性，我们将更好地了解信息在嗅觉系统中是如何处理的。在此应用中，我们重点关注脊椎动物嗅觉系统中表达的“C 家族”G 蛋白偶联受体的特性。该受体家族包括哺乳动物犁鼻系统的假定信息素感应受体和鱼类嗅觉系统的氨基酸感应受体。我们的研究包括三个研究方向：（1）基于相关受体的已知结构，我们将对由氨基酸（对鱼类有效的气味剂）激活的金鱼气味受体的配体结合口袋进行分子建模和功能验证。通过这种方法，我们将确定配体和受体之间的关键相互作用，这些相互作用提供分子特异性并导致气味受体激活。 (2) 为了解开用于编码嗅觉信息的受体组合，我们将从金鱼和斑马鱼中分离出额外的 C 家族嗅觉受体，并鉴定它们的同源配体。通过表征更广泛的气味受体集合的分子特异性，我们将更清楚地理解如何组合使用多种受体来识别和区分气味。 (3) 最近的证据表明，一些气味受体可以在同一感觉神经元内共表达。多个受体是否在细胞内独立发挥作用，或者它们是否形成异聚复合物，其配体特异性是分子间相互作用的新兴特性？我们将确定 C 家族嗅觉受体的成员是否形成寡聚复合物，以及受体功能的各个方面（包括配体特异性、信号转导和细胞内运输）是否在异源寡聚复合物中发生改变。这些研究将有助于确定受体寡聚化在确定嗅觉感觉神经元的反应特异性和使其多样化方面发挥什么作用（如果有的话）。我们的研究将有助于阐明嗅觉编码的分子和细胞机制。