Characterizing the role of TRPM4 in taste transduction

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Chemical sensory systems, which are comprised of olfaction and taste in vertebrates and many invertebrates, play important roles in feeding and social interactions. The sense of taste is used to determine whether potential food items will be ingested or rejected and is critical for an organism’s survival. Because the chemicals that activate the taste system have variable structures, there are multiple taste cell types that use different signaling pathways to detect these stimuli. Some taste chemicals activate receptors that initiate second messenger cascades, while others interact directly with ion channels to cause a cellular response. The PI’s laboratory has recently reported that the monovalent selective TRP channel, TRPM4, has a critical role in taste transduction but how it functions in taste cells is poorly understood. The goal of this application is to characterize how TRPM4 contributes to taste transduction in the different signaling pathways. Overall, the current understanding of the fundamental mechanisms that translate taste stimuli into a signal that is sent to the brain for processing is still quite limited. Therefore, a better characterization of these signaling pathways will provide an enhanced understanding of how taste information is sent to the brain and more generally, provide new insights into how the brain gathers information about its surroundings. The project will also support the PI's efforts to increase the number of underrepresented groups to pursue careers in STEM through the University at Buffalo’s Collegiate Science and Technology Entry Program (CSTEP).Taste stimuli activate multiple signaling mechanisms in distinct taste cells populations within the oral cavity. One cell population communicates via conventional synapses and expresses voltage-gated calcium channels (VGCCs). A different cell population lacks chemical synapses and relies on the phospholipase-C-dependent signaling pathway to activate a Calhm1/3 channel complex to release neurotransmitter. Taste cells that express this pathway (called Type II cells) contribute to the detection of bitter, sweet and umami taste stimuli. Taste cells with conventional synapses (Type III cells) detect sour and salty stimuli. Recently, it is becoming clear that the signaling pathways in these different cell types are more complex than previously appreciated. The PI’s laboratory identified a critical role for the transient receptor potential melastatin 4 channel (TRPM4) in the Type II signaling pathways and reported that TRPM4 is also expressed in Type III cells. Initial data has found that the role of TRPM4 varies within the different signaling pathways and is differentially used to affect the output response. How this happens and the modulators regulating TRPM4 activity in these different cell populations is unknown. The proposal’s focus is to define the function of TRPM4 in different taste signaling pathways and to identify how it is regulated in each. The specific aims are: (1) How is TRPM4 regulated in the GPCR signaling pathway in Type II cells? and (2) What is the role of TRPM4 in ionotropic signaling in Type III cells? These aims will be accomplished using mouse transgenics, live cell imaging and pharmacological approaches.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.