Modulation of Odorant Receptor Function

描述（由申请人提供）：哺乳动物的气味感知是一个复杂的过程，其由称为气味受体（OR）的G蛋白偶联受体（GPCR）家族的激活介导，所述气味受体表达于排列在嗅觉上皮上的数百万个嗅觉感觉神经元（OSN）的纤毛上.嗅上皮丰富的自主神经支配， 包括释放乙酰胆碱的副交感神经末梢。我们最近发现，OSN表达3型毒蕈碱乙酰胆碱受体（M3R），另一种GPCR。然而，胆碱能作用于OSN的分子机制还不清楚。 我们提出的实验，以解决嗅觉调制的重要性，并澄清的乙酰胆碱受体对OSN信号的影响的分子机制。这项工作将进一步了解信息处理如何发生在嗅觉的最早阶段。为了验证M3R对OR功能和嗅觉信号转导的调节是重要的假设，提出了以下具体目的：目的1。验证M3受体调节嗅觉神经元功能的假设。为了验证M3R参与气味介导的替代信号激活的假设，目的3。鉴定M3R的结构域和对M3R和OR的功能相互作用重要的信号传导组分。所提出的实验进一步实现了我们的长期目标，即理解调节气味受体功能的机制基础。 这些研究的健康相关性在于，更好地理解OR和下游信号转导的调节机制将提供对GPCR信号传导的一般特征的见解，GPCR是心脏病、精神病和癌症疾病最常见的药物靶点。这项工作将推进我们对G蛋白偶联OR如何受另一种GPCR M3R调节的理解，M3R由乙酰胆碱激活，乙酰胆碱是副交感神经系统的关键神经递质。了解神经递质受体和外周嗅觉系统之间的相互作用提供了重要的信息，可能有助于对嗅觉受损的嗅觉缺失和嗅觉减退患者进行新的治疗，并减少与恶臭相关的压力，改善他们的生活质量。

DESCRIPTION (provided by applicant): Odor perception in mammals is a complex process mediated by the activation of a family of G- protein coupled receptors (GPCRs) known as odorant receptors (ORs) expressed at the cilia of millions of olfactory sensory neurons (OSNs) lining the olfactory epithelium. The olfactory epithelium is richly innervated by autonomic nerves, including parasympathetic nerve endings which release acetylcholine. We recently discovered that OSNs express the type 3 muscarinic acetylcholine receptor (M3R), another GPCR. However, the molecular mechanisms underlying cholinergic actions on OSNs are not well-understood. We propose experiments to address the importance of modulation of olfaction and to clarify the molecular mechanisms that underlie the effects of acetylcholine receptors on OSN signaling. This work will further our understanding of how information processing occurs during the earliest steps of olfaction. To test the hypothesis that the M3R is important for the regulatio of OR function and olfactory signal transduction, the following Specific Aims are proposed: Aim 1. To test the hypothesis that M3R modulates the function of olfactory sensory neurons Aim 2. To test the hypothesis that M3R is involved in odor-mediated activation of alternative signaling Aim 3. To identify structural domains of M3R and signaling components important for the functional interaction of M3R and OR The proposed experiments further our long term goal, which is to understand the mechanistic basis for regulation of odorant receptor function. The health relatedness of these studies is that a better understanding of the regulatory mechanism of ORs and downstream signal transduction will offer insights into the general features of signaling by GPCRs, the most frequent pharmaceutical targets for cardiac, psychiatric, and cancer diseases. This work will advance our understanding on how G protein-coupled ORs are regulated by another GPCR, M3R, which is activated by acetylcholine, the key neurotransmitter of the parasympathetic nervous system. An understanding of the interactions between the neurotransmitter receptor and the peripheral olfactory system provides crucial information that may contribute toward novel therapy for anosmic and hyposmic patients who have compromised sense of smell, and to reduce stress associated with malodor, improving their quality of life.