Molecular Genetics of Taste Transduction

描述（由申请人提供）：味觉形态不仅对帮助识别食物至关重要，而且对避免食用有毒化学物质也至关重要。这项研究的长期目标是了解果蝇（Drosophila melanogaster）甜味和苦味转导的分子机制。果蝇已被证明是一个有价值的模式生物表征其他感官的方式，如视觉和嗅觉，然而，味觉转导已收到较少的审查。最近的研究表明，哺乳动物和果蝇的味觉信号转导途径是由G蛋白偶联受体启动的.然而，果蝇受体下游的运作机制在很大程度上是未知的。在哺乳动物中，有证据表明味觉转导通过磷脂酶C介导的信号传导途径进行，该途径以TRPM 5通道的激活而达到高潮。然而，许多问题仍然存在，包括适应的机制，cAMP信号在味觉传导中的作用，味觉通道的调节机制，在体内和味觉受体的调节蛋白。拟议研究的目标是在果蝇中应用遗传、电生理、细胞和生物化学方法的组合，以确定由有吸引力或厌恶性化合物引发的味觉转导的生物化学基础。本提案的具体目的是检验以下假设：1）参与果蝇视觉的PI信号蛋白也在味觉中起作用，2）cAMP信号在果蝇甜和苦的转导中起作用，3）Gr66 a是咖啡因受体，该受体的错误表达可以引起对咖啡因的吸引性行为反应，TRPA 2味觉通道受钙调蛋白和支架蛋白Homer相互作用的调节。鉴于哺乳动物和果蝇味觉转导之间的明显相似之处，这些研究应该提供重要的新的见解味觉转导机制，适用于人类味觉受体细胞。

DESCRIPTION (provided by applicant): The taste modality is critical not only to aid in the identification of food, but also to avoid consuming noxious chemicals. The long-term goal of the proposed research is to understand the molecular mechanisms underlying sweet and bitter taste transduction in the fruitfly, Drosophila melanogaster. The fruitfly has proven to be a valuable model organism for characterizing other sensory modalities, such as vision and olfaction; however, taste transduction has received less scrutiny. Recent studies indicate that the mammalian and Drosophila taste transduction pathways are initiated by G- protein coupled receptors. However, the mechanisms operating downstream of the Drosophila receptors are largely unknown. In mammals, there is evidence that taste transduction operates through a phospholipase C mediated signaling pathway that culminates with the activation of the TRPM5 channel. Nevertheless, many questions remain including the mechanisms of adaptation, the role of cAMP signaling in taste transduction, the mechanisms that regulate the gustatory channel in vivo and the proteins regulating the gustatory receptors. The goal,of the proposed research is to apply a combination of genetic, electrophysiological, cell and biochemical approaches in Drosophila to define the biochemical basis for taste transduction initiated by either attractive or aversive compounds. The specific aims of this proposal are to test the hypotheses that: 1) the PI signaling proteins involved in Drosophila vision also function in taste, 2) cAMP signaling functions in Drosophila sweet and bitter transduction, 3) Gr66a is the caffeine receptor and misexpression of this receptor can elicit an attractive behavioral response to caffeine, and 4) the TRPA2 gustatory channel is regulated by calmodulin and interactions with the scaffold protein Homer. Given the apparent parallels between mammalian and Drosophila taste transduction, these studies should provide important new insights into the mechanisms of gustatory transduction that apply to human taste receptor cells.