Expression and characterization of the TRPM8 receptor in lung epithelial cells

Temperature sensation plays a vital role in maintaining homeostasis and dictates our responses to the environment. Several members of the Transient Receptor Potential (TRP) family of ion channels have been identified as temperature sensors, responding to alterations in temperature and chemical agonists such as menthol, capsaicin etc., that elicit sensations of temperature changes. TRPM8, a member of the TRP superfamily, is a cold and menthol sensing ion channel that acts by converting thermal and chemical stimuli into neuronal signals. Although significant literature exists regarding TRPM8 function in sensory processes, the expression and function of TRPM8 in non-neuronal tissues are currently unknown. This dissertation explores the hypothesis that TRPM8 mediates airway epithelial responses to cold air/temperatures.;Inhaling cold air for prolonged periods is detrimental to the human airways. Neuronal responses cannot account for all such cold-induced responses. Our findings support the existence of an alternate, nonneuronal cold response pathway in the lung epithelial cells, suggesting that nonneuronal cold temperature transduction may be a more common theme in mammalian homeostasis than is currently appreciated. The major biomedical application of this dissertation is that TRPM8 activation within respiratory epithelial cells could provide an effective mechanism for modulation of physiological responses of the human airways to cold air/temperature. Furthermore, our results indicate that aberrant TRPM8 function and its downstream pathways may participate in certain cold-induced respiratory diseases, such as asthma. If this were true, then TRPM8 activation and its downstream response elements could provide potential new targets of drug development for cold-induced respiratory diseases.;In this dissertation, we demonstrate that TRPM8 is expressed in human bronchial epithelial cells. Functional integrity of TRPM8 in lung cells is also ascertained using the prototypical TRPM8 agonist menthol and cold temperatures. Results show the exclusive expression of a novel TRPM8 variant isoform, lacking the N-terminal region, in lung epithelial cells. In addition, prolonged activation of the TRPM8 variant receptor lead to enhanced production of various proinflammatory cytokines, suggesting a role for this receptor in cellular inflammatory responses mediated by cold air/temperature. Cold-induced asthmatic responses may be an intriguing and highly important example of TRPM8-mediated inflammation.