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Human Lung Epithelial Cells Express a Functional Cold-Sensing TRPM8 Variant

¹ Department of Pharmacology and Toxicology, and ² Department of Chemistry, University of Utah, Salt Lake City, Utah

Correspondence and requests for reprints should be addressed to Christopher A. Reilly, Ph.D., University of Utah, Department of Pharmacology and Toxicology, 30 South, 2000 East, Skaggs Hall, Room 201, Salt Lake City, UT 84112. E-mail: Chris.Reilly{at}pharm.utah.edu

Several transient receptor potential (TRP) ion channels sense and respond to changes in ambient temperature. Chemical agonists of TRP channels, including menthol and capsaicin, also elicit sensations of temperature change. TRPM8 is a cold- and menthol-sensing ion channel that converts thermal and chemical stimuli into neuronal signals and sensations of cooling/cold. However, the expression and function of TRPM8 receptors in non-neuronal cells and tissues is a relatively unexplored area. Results presented here document the expression and function of a truncated TRPM8 variant in human bronchial epithelial cells. Expression of the TRPM8 variant was demonstrated by RT-PCR, cloning, and immunohistology. Receptor function was characterized using the prototypical TRPM8 agonist, menthol, and exposure of cells to reduced temperature (18°C). The TRPM8 variant was expressed primarily within endoplasmic reticulum membranes of lung epithelial cells and its activation was attenuated by thapsigargin, the cell-permeable TRPM8 antagonist N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide, and shRNA-induced suppression of TRPM8 expression. Activation of the TRPM8 variant in lung cells was coupled with enhanced expression of the inflammatory cytokines IL-6 and IL-8. Collectively, our results suggest that this novel TRPM8 variant receptor may function as a modulator of respiratory physiology caused by cold air, and may partially explain asthmatic respiratory hypersensitivity to cold air.

Key Words: TRP family • TRPM8 • menthol • calcium • lung epithelial cells

CLINICAL RELEVANCE This research characterizes a transient receptor potential melastatin 8 (TRPM8) variant that effects IL-6 and IL-8 expression by lung epithelial cells. These data provide a rationale for translational research evaluating the role of TRPM8 in respiratory distress due to cold air inhalation.