Control of homeostasis by trace amine-associated receptors

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My long-term goal is to determine the physiological roles of endogenous chemicals called trace amines and the proteins (trace amine-associated receptors; TAAR) that detect their presence. TAAR are present throughout the body in all vertebrate species, but with the exception of TAAR1 in the brain, little is known about their normal roles. Two of the most prominent sites of TAAR outside of the brain are the nasal passages and the pancreas. Unlike many other receptors, TAAR are not present at cell surfaces, rather residing inside the cell. This requires that trace amines cross cell membranes in order to bind to TAAR and participate in cell-cell communication. Our previous work has shown that this process is controlled by transporters that have not yet been identified. With respect to their role in the sense of smell, TAAR detect odours from diverse ecological sources including predators, spoiled food, and even putative pheromones. This detection causes innate behaviours (no learning is necessary) that are gender and species dependent, but the cellular basis of these effects are unknown. Our previous work showing trace amines readily cross cell membranes suggests effects may also occur due to trace amines crossing lung membranes following inhalation. Effects due to inhaled trace amines entering the bloodstream have not previously been considered. Our initial studies indicate that blood glucose levels are altered in response to inhalation of some, but not all, trace amines. We have also confirmed that in the pancreas TAAR control insulin release. How TAAR do this, however, is unknown. To progress toward our long-term goal, and address the knowledge gaps identified above, the studies in this proposal will: 1) identify the transporters that control trace amine access to TAAR, 2) determine the role of TAAR in adaptive responses to environmental stressors of different ecological origins, and 3) determine the molecular mechanism of TAAR regulated insulin release. By filling these knowledge gaps new molecular targets for the regulation of trace amine function will be identified, which is crucial to elucidating the role of trace amine physiology in maintaining body functions. Identification of these targets will also be critical to future translational research by those investigating human disorders such as post-traumatic stress disorder, diabetes and obesity. Further, by determining the molecular basis of gender and species specific responses to chemicals associated with ecological hazards, some of which have life-or-death consequences, we will increase the understanding of adaptive stress responses in vertebrates, and the molecular basis of their physiological adaptations to habitat changes and ecological challenges.