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.