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。这些味道是由g蛋白偶联的味觉受体检测到的，该受体启动信号级联，其中酶PLC22和离子通道TRPM5是必不可少的元素。据推测，TRPM5在PI(4,5)P2水解成IP3和DAG的下游被激活，通过释放细胞内储存的Ca2+。我们最近的研究结果表明，小鼠味觉受体细胞中的trpm5依赖电流被细胞内Ca2+激活，并响应细胞内Ca2+脱敏。这些结果提出了以下问题，将在本拨款申请中解决(1)Ca2+是味觉转导的第二信使，耦合受体信号到电反应和递质释放？(2) TRPM5是否与Ca2+信号通路的元件存在功能关联？(3) TRPM5脱敏的生化或结构事件是什么？总之，这些实验将使我们能够开发出TRPM5通道对味觉信号传导的贡献模型。味觉在决定对食物和药物的接受度方面起着重要作用，因此有选择地调节味觉的能力可以带来显著的健康益处。味觉在决定食品和药品的接受度方面起着重要作用。通过了解味觉的信号通路，关键的分子事件是什么，它们是如何在空间中组织的，以及它们是如何随时间变化的，我们可以更好地开发出改变味觉的方法来增加或减少感觉。此外，味觉细胞中信号通路的信息可以为理解味觉如何随着发育和衰老或对疾病的反应而变化提供基础。

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.