TRP ion channels in taste transduction

描述（由申请人提供）：在此资助下进行的研究旨在了解介导苦，甜和鲜味转导的第二信使门控离子通道。这些味道被G蛋白偶联的味觉受体检测到，该味觉受体启动信号级联，酶PLC 22和离子通道TRPM 5是该信号级联的必需元件。假设TRPM5在PI（4，5）P2水解为IP3和DAG的下游通过从细胞内储存释放Ca2+而被激活。我们最近的研究结果表明，TRPM5依赖性电流在小鼠味觉受体细胞被激活，并脱敏，细胞内Ca 2+。这些结果提出了以下问题，这些问题将在本基金申请中解决（1）Ca 2+是味觉传导的第二信使，将受体信号传导耦合到电反应和递质释放吗？(2)TRPM5与Ca2+信号通路的元件是否存在功能关联？TRPM5脱敏的生物化学或结构事件是什么？这些实验将使我们能够开发TRPM5通道对味觉信号的贡献模型。味觉在决定食物和药物的接受程度方面起着重要作用，因此选择性调节味觉的能力可以带来显着的健康益处。公共卫生相关性味觉在决定食品和药物的接受程度方面起着重要作用。通过了解味觉背后的信号通路，关键的分子事件是什么，它们在空间中是如何组织的，以及它们如何随时间变化，我们可以更好地开发出改变味觉以增加或减少感觉的方法。此外，有关味觉细胞中信号通路的信息可以形成理解味觉如何随着发育和衰老或对疾病的反应而变化的基础。

DESCRIPTION (provided by applicant): Studies conducted under this grant are directed at understanding the second messenger-gated ion channels that mediate the transduction of bitter, sweet and umami taste. These tastes are detected by G-protein-coupled taste receptors that initiate a signaling cascade for which the enzyme PLC22 and the ion channel TRPM5 are essential elements. It is hypothesized that TRPM5 is activated downstream of hydrolysis of PI(4,5)P2 to IP3 and DAG, by the release of Ca2+ from intracellular stores. Our recent results show that the TRPM5-dependent current in mouse taste receptors cells is activated by, and desensitizes in response to, intracellular Ca2+. These results raise the following questions which will be addressed in this grant application (1) Is Ca2+ the second messenger for taste transduction, coupling receptor signaling to an electrical response and transmitter release? (2) Is there a functional association of TRPM5 with elements of the Ca2+ signaling pathway? and (3) What are the biochemical or structural events that underlie desensitization of TRPM5? Together these experiments will allow us to develop a model for the contribution of TRPM5 channels to taste signaling. Taste plays an important role in determining the acceptance of foods and drugs and the ability to selectively modulate taste can therefore lead to significant health benefits. PUBLIC HEALTH RELEVANCE Taste plays an important role in determining the acceptance of foods and drugs. By understanding the signaling pathways that underlie taste sensation, what the key molecular events are, how they are organized in space, and how they change over time, we can better develop ways to modify taste to increase or decrease sensation. Moreover, information about the signaling pathways in taste cells can form the basis for understanding how taste sensation changes with development and aging or in response to disease.