Phosphoinositide Signaling in Mammalian Olfaction

哺乳动物嗅觉中的磷酸肌醇信号转导

• 批准号: 6729120
• 负责人: Barry W. ACHE
• 金额: $ 26.45万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6729120
• 关键词: biological signal transduction; calcium flux; cell line; chemoreceptors; enzyme activity; high performance liquid chromatography; immunocytochemistry; laboratory mouse; laboratory rat; odors; olfactions; olfactory stimulus; phosphatidylinositol 3 kinase; phosphatidylinositols; respiratory epithelium; voltage /patch clamp; western blottings

DESCRIPTION (provided by applicant): Odors play an increasingly appreciated role in our general quality of life and well being, a role that is compromised by the effect of disease, drugs, aging and environmental onslaught on the olfactory epithelium. Primary receptor neurons in the olfactory epithelium serve the critical function of detecting and transducing odor stimuli. Disruption of any of the cellular processes leading to receptor cell activation would impair olfactory function. New findings on which this project is built underscore earlier, inconclusive evidence that the process by which odorants activate mammalian olfactory receptor cells may be more complex than originally appreciated. These findings show that blocking the phosphoinositide-3 kinase (PI3K)-mediated arm of the phosphoinositide signaling pathway enhances odorant-evoked increases in intracellular calcium in rat olfactory receptor cells in an odorant-specific manner, and suggest that phosphoinosotide signaling modulates odorant-evoked excitation of mammalian olfactory receptor cells in the context of odorant coding. The presence of a second intracellular signaling pathway activated in an odorant-specific manner would allow the receptor cell to actually integrate the signal that establishes the combinatorial code on which odor recognition is based. A series of focused, primarily electrophysiological and imaging-based experiments address this novel idea by further characterizing the effect of blocking PI3K on the response of rat and mouse olfactory receptor neurons, by beginning to characterize the cellular mechanisms by which PI3K modulates the output of the cells, and by further characterizing the functional significance of this modulation. The results of the project can be expected to clarify the long-suspected, but elusive role of phosphoinositide signaling in mammalian olfaction, and provide a more complete understanding of the role of the olfactory periphery in how odorants are encoded by the nervous system.

描述（由申请人提供）：气味在我们的总体生活质量和健康中发挥着越来越重要的作用，但疾病、药物、衰老和环境对嗅觉上皮细胞的影响会损害这种作用。嗅觉上皮中的初级受体神经元起着检测和传导气味刺激的关键功能。任何导致受体细胞激活的细胞过程的破坏都会损害嗅觉功能。该项目所依据的新发现强调了早期的非决定性证据，即气味剂激活哺乳动物嗅觉受体细胞的过程可能比最初想象的更复杂。这些发现表明，阻断磷酸肌醇信号通路中磷酸肌醇 3 激酶 (PI3K) 介导的臂可以以气味特异性方式增强大鼠嗅觉受体细胞中气味诱发的细胞内钙的增加，并表明磷酸肌醇信号传导可调节气味诱发的钙离子浓度。在气味编码的背景下激发哺乳动物嗅觉受体细胞。以气味特异性方式激活的第二个细胞内信号传导途径的存在将允许受体细胞真正整合信号，从而建立气味识别所基于的组合代码。一系列集中的、主要基于电生理学和成像的实验通过进一步表征阻断 PI3K 对大鼠和小鼠嗅觉受体神经元反应的影响，通过开始表征 PI3K 调节嗅觉受体神经元输出的细胞机制，解决了这一新想法。细胞，并进一步表征这种调节的功能意义。该项目的结果有望澄清磷酸肌醇信号在哺乳动物嗅觉中的长期怀疑但难以捉摸的作用，并提供对嗅觉周围在神经系统如何编码气味中的作用的更完整的理解。