Phosphoinositide Signaling in Mammalian Olfaction

描述(申请人提供)：气味在我们的一般生活质量和福祉中扮演着越来越重要的角色，这个角色因疾病、药物、衰老和环境对嗅觉上皮的冲击而受到影响。嗅觉上皮中的初级感受器神经元起着探测和传递气味刺激的关键作用。任何导致受体细胞激活的细胞过程的中断都会损害嗅觉功能。这个项目建立在新发现的基础上，强调了早期的非确凿证据，即气味激活哺乳动物嗅觉感受器细胞的过程可能比最初意识到的更加复杂。这些发现表明，阻断磷脂酰肌醇-3激酶(PI3K)介导的肌醇磷脂信号通路的臂以气味特异性的方式增强气味诱导的大鼠嗅觉受体细胞内钙的增加，并提示磷酸肌苷信号在气味编码的背景下调制气味诱导的哺乳动物嗅觉受体细胞的兴奋。以气味特有的方式激活的第二个细胞内信号通路的存在，将允许受体细胞实际上整合建立气味识别所基于的组合代码的信号。一系列集中的、主要基于电生理和成像的实验解决了这一新想法，通过进一步表征阻断PI3K对大鼠和小鼠嗅觉感受器神经元反应的影响，开始表征PI3K调节细胞输出的细胞机制，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长期以来一直怀疑但难以捉摸的肌醇磷脂信号在哺乳动物嗅觉中的作用，并提供更全面的了解嗅觉外周在神经系统如何编码气味方面的作用。

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.