Regulation of Olfactory Signal Transduction

描述（由申请人提供）：嗅觉转导是嗅觉感觉神经元（OSNs）将气味信息转化为神经元电信号的过程。在过去的25年里，广泛的研究已经导致脊椎动物osn核心转导途径的阐明。然而，调节转导以允许适当的敏感性和反应动力学的过程尚未得到很好的理解。钙是一种关键的嗅觉传导调节剂。在嗅觉响应过程中，钙通过嗅觉环核苷酸门控（CNG）通道进入感觉纤毛，放大OSN去极化，并负调控几种嗅觉转导成分。这种负调节控制着OSN的适应性，这种现象表现为对持续或重复刺激的敏感性降低。在本提案中，我们建议利用我们产生的多个转基因小鼠品系：1)研究多种Ca2+依赖的反馈机制在OSN适应中的整合（Aim 1）；2)研究在终止和适应中起作用的负调节机制在设置OSN敏感性方面的作用（目的2）。电生理分析，在水平上

DESCRIPTION (provided by applicant): Olfactory transduction is the process by which olfactory sensory neurons (OSNs) transform odor information into neuronal electrical signals. Over the past two and a half decades, extensive investigations have led to the elucidation of a core transduction pathway in vertebrate OSNs. However, the processes that regulate transduction to allow for proper sensitivity and response kinetics are not well understood. Calcium is a key olfactory transduction regulator. Calcium enters the sensory cilium through the olfactory cyclic nucleotide-gated (CNG) channel during the odor response, amplifies OSN depolarization, and also negatively regulating several olfactory transduction components. This negative regulation governs OSN adaptation--a phenomenon manifested as reduced sensitivity upon sustained or repeated stimulation. In this proposal, we propose to take advantage of multiple genetically modified mouse strains that we generated to: 1) investigate the integration of multiple Ca2+-dependent feedback mechanisms in OSN adaptation (Aim 1); and 2) investigate the role of negative regulatory mechanisms, which function in termination and adaptation, in setting OSN sensitivity at rest (Aim 2). Electrophysiological analysis, at the level of intact olfactory epithelium and the isolated single cell level, will be conducted on mice carrying double or triple mutations for calcium-dependent feedback mechanisms (Aim 1) as well as on mice that lack a calcium-dependent feedback mechanism and also lack efficient calcium extrusion (Aim 2). The long-term goal of this proposal is to elucidate the molecular mechanisms underlying olfaction. The proposed investigation will lead to a better understanding of how OSNs encode the intensity and temporal features of odor stimulations by regulating sensitivity and response kinetics. The knowledge gained from the proposed research will enhance our understanding of normal olfactory function and olfactory dysfunctions.