Phosphoinositide Signaling in Mammalian Olfaction

气味在我们的一般生活质量和健康中发挥着越来越重要的作用， 受到疾病、药物、老化和环境对嗅上皮冲击的影响。 嗅上皮中的初级受体神经元起着检测和传递信息的重要作用 气味刺激任何导致受体细胞活化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， 气味剂激活哺乳动物嗅觉受体细胞的过程可能比 最初欣赏。这些发现表明，阻断磷酸肌醇-3激酶（PI 3 K）介导的 磷酸肌醇信号通路的一个分支增强了气味诱发的细胞内钙的增加， 大鼠嗅觉受体细胞的气味特异性的方式，并建议磷酸肌醇信号 在气味编码的背景下调节哺乳动物嗅觉受体细胞的气味诱发的兴奋。 以气味特异性方式激活的第二种细胞内信号传导途径的存在将 使受体细胞能够整合信号， 认知是有基础的。一系列重点突出的，主要是电生理和成像实验 通过进一步表征阻断PI 3 K对大鼠反应的影响来解决这一新想法， 小鼠嗅觉受体神经元，通过开始表征PI 3 K 调节细胞的输出，并通过进一步表征这种调节的功能意义。 该项目的结果有望澄清长期怀疑，但难以捉摸的作用，磷酸肌醇 信号在哺乳动物的嗅觉，并提供了一个更完整的理解的作用，嗅觉 神经系统如何编码气味的外围。

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.