TY - JOUR T1 - Transient Receptor Potential Ankyrin-1 (TRPA1) and Vanilloid-3 (TRPV3) Differentially Regulate Endoplasmic Reticulum Stress and Cytotoxicity in Human Lung Epithelial Cells Following Pneumotoxic Wood Smoke Particle Exposure JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.120.000047 SP - MOLPHARM-AR-2020-000047 AU - Nam D. Nguyen AU - Tosifa A. Memon AU - Katherine L. Burrell AU - Marysol Almestica-Roberts AU - Emmanuel Rapp AU - Lili Sun AU - Abigail F. Scott AU - Cassandra Deering-Rice AU - Joseph E. Rower AU - Christopher A. Reilly Y1 - 2020/01/01 UR - http://molpharm.aspetjournals.org/content/early/2020/09/12/molpharm.120.000047.abstract N2 - This study investigated the roles of Transient Receptor Potential Ankyrin-1 (TRPA1) and TRP Vanilloid-3 (TRPV3) in regulating endoplasmic reticulum stress (ERS) and cytotoxicity in human bronchial epithelial cells (HBECs) treated with pneumotoxic wood smoke particulate matter (WSPM) and chemical agonists of each channel. Functions of TRPA1 and TRPV3 in pulmonary epithelial cells remain largely undefined. This study shows that TRPA1 activity localizes to the plasma membrane and ER of cells, whereas TRPV3 resides primarily in the ER. Additionally, treatment of cells using moderately cytotoxic concentrations of pine WSPM, carvacrol, and other TRPA1 agonists, caused ERS as a function of both TRPA1 and TRPV3 activities. Specifically, ERS and cytotoxicity were attenuated by TRPA1 inhibition, while inhibiting TRPV3 exacerbated ERS and cytotoxicity. Interestingly, following treatment with pine WSPM, TRPA1 transcription was suppressed, while TRPV3 was increased. TRPV3 overexpression in HBECs conferred resistance to ERS and an attenuation of ERS-associated cell cycle arrest caused by WSPM and multiple prototypical ERS-inducing agents. Alternatively, shRNA-mediated knockdown of TRPV3, like the TRPV3 antagonist, exacerbated ERS. This study reveals previously undocumented roles for TRPA1 in promoting pathological ERS and cytotoxicity elicited by pneumotoxic WSPM and TRPA1 agonists, and a unique role for TRPV3 in fettering pathological facets of the integrated ERS response. Significance Statement These findings provide new insights into how WSPM and other TRPA1 and TRPV3 agonists can affect HBECs, and highlight novel physiological and pathophysiological roles for TRPA1 and TRPV3 in these cells. ER -