Transient receptor potential vanilloid member 1 (TRPV1) is a membrane protein ion channel that functions as a heat and capsaicin receptor. In addition to activation by hot temperature and vanilloid compounds such as capsaicin, TRPV1 is modulated by various stimuli including acidic pH, endogenous lipids, diverse biological and synthetic chemical ligands, and modulatory proteins. Due to its sensitivity to noxious stimuli such as high temperature and pungent chemicals, there has been significant evidence that TRPV1 participates in a variety of human physiological and pathophysiological pathways, raising the potential of TRPV1 as an attractive therapeutic target. However, the polymodal nature of TRPV1 function has complicated clinical application because the TRPV1 activation mechanisms from different modes have generally been enigmatic. Consequently, tremendous efforts have put into dissecting the mechanisms of different activation modes, but numerous questions remain to be answered.

The studies conducted in this dissertation probed the role of the S1-S4 membrane domain in temperature and ligand activation of human TRPV1. Temperature-dependent solution nuclear magnetic resonance (NMR) spectroscopy for thermodynamic and mechanistic studies of the S1-S4 domain. From these results, a potential temperature sensing mechanism of TRPV1, initiated from the S1-S4 domain, was proposed. Additionally, direct binding of various ligands to the S1-S4 domain were used to ascertain the interaction site and the affinities (Kd) of various ligands to this domain. These results are the first to study the isolated S1-S4 domain of human TRPV1 and many results indicate that the S1-S4 domain is crucial for both temperature-sensing and is the general receptor binding site central to chemical activation.

The prevalence of excessive weight gain (obesity) has steadily increased since about 1980. Excessive weight gain is associated with many comorbidities; thus, a successful treatment is needed. The most common form of non-surgical treatment for excessive weight gain is caloric restriction with the intent to reduce body weight by 10%. Though this treatment is successful at reducing body weight, it often fails at maintaining the weight loss. Dietary menthol has been suggested as a possible treatment for excessive weight gain and has produced promising results as a preventative method for excessive weight gain. Our studies aimed at reducing weight regain and maintaining caloric restriction by feeding male Sprague-Dawley rats 0.5% dietary menthol during a period of caloric restriction, aimed at reducing their body weight by 10%, following an experimental period where the rats were fed a high-fat diet (HFD) or low-fat diet (LFD). The effects of the dietary menthol were observed during the weight regain period following the caloric restriction period. Two studies were conducted, and both were unable to achieve a maintenance of weight loss following caloric restriction, although our first study was able to produce a delay in weight regain and did not show any evidence of increased thermogenesis in menthol-treated rats. Our findings differ from the findings of previous studies on dietary menthol which could possibly be due to species effects, differences in procedures, age effects, or effects of different fatty acid compositions. The contrasting results in our studies could be due to genetic differences between litters used or a difference in manufacturing of the menthol diet between studies. Given the partial response to menthol in the first study, it can be suggested that the concentration of 0.5% may be below the threshold of menthol sensitivity for some rats. Future research should focus on increasing the concentration of dietary menthol from 0.5% to 1%, since the current concentration did not yield a reduction in weight regain or maintenance of caloric restriction.