Yali V. Zhang, Ph.D. - US grants

? DESCRIPTION (provided by applicant): Food texture, which includes hardness, softness and viscosity, plays an indispensible role in controlling an animal?s taste preference. The texture of food is primarily detected through mechanosensory receptors located in taste organs. Although food texture has enormous impact on food intake behavior, the molecular and cellular identities of mechanosensory receptors responsible for food texture sensation are largely unknown. Transmembrane channel-like (TMC) proteins are highly conserved from worms to flies, mice and humans, and are proposed to be cation channels. However, definitive evidence is lacking. A common theme is that TMC proteins appear to mediate different forms of mechanosensation. For instance, both dominant and recessive mutations affecting TMC1 result in severe hearing impairments in mice and humans. Moreover, our preliminary data suggest that fly TMC is a mechanosensor, which is critical for discriminating foods on the basis of texture. Here, I propose to use the fruit fly as a model organism to dissect the molecular and cellular mechanisms through which mechanical properties of food affect taste preferences. Firstly, I will explore how mechanical force is encoded by tmc-expressing neurons in the peripheral taste organ of fruit fly. Secondly, I will test if the tmc expressing cell is sufficient to act as a mechanosensory neuron. Thirdly, I propose to determine the membrane trafficking and force gating mechanisms of TMC ion channels. In summary, this proposal will test the hypothesis that fly TMC is a mechanosensor dictating food texture sensation, and that TMC defines previously unknown mechanosensory neurons required for detecting food texture in fruit flies.

Abstract Animals ranging from insects to mammals employ specific taste receptors to perceive distinct food flavors, such as sweet, bitter, sour, and salty. In contrast to other basic taste modalities, salty and sour tastes are primarily mediated through sodium and proton ion channels, respectively. Animals normally prefer low levels of salt or acid and reject high concentrations. Since salt and acid are important mineral nutrients, insufficient or excessive consumption of salt or acid can lead to gastrointestinal, metabolic, and cardiovascular diseases. Although salty and sour tastes have a profound impact on human health, the molecular identities of salty and sour taste receptors have not been fully determined. In addition, the neuronal circuits underlying salt taste response and intake are unknown. Using the fruit fly, Drosophila melanogaster, as a model organism, our previous work identified a new ionotropic glutamate receptor that is required for high-salt sensation. Additionally, we found that a small subset of neurons in the fly brain regulate high-salt avoidance. Moreover, we discovered that a novel ion channel, which can be directly activated by protons, is required for the attractive sour taste response in flies. Building on our preliminary findings, we propose to use the fruit fly as a model organism to explore the molecular and neural mechanisms of salty and sour taste perception. In particular, we will pursue two principal lines of inquiry: (1) decipher the molecular and neural mechanisms of salty taste sensation; and (2) decipher the molecular basis of sour taste sensation. Given that taste transduction mechanisms to salt and acid are analogous between flies and mammals, the molecular insights gleaned from our research in fruit flies will inform studies of salty and sour taste sensations in mammals, including humans.