PT  - JOURNAL ARTICLE
AU  - John G. Lamb
AU  - Erin G. Romero
AU  - Zhenyu Lu
AU  - Seychelle K. Marcus
AU  - Hannah C. Peterson
AU  - John M. Veranth
AU  - Cassandra E. Deering-Rice
AU  - Christopher A. Reilly
TI  - Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells
AID  - 10.1124/mol.117.109959
DP  - 2017 Jan 01
TA  - Molecular Pharmacology
PG  - mol.117.109959
4099  - http://molpharm.aspetjournals.org/content/early/2017/10/16/mol.117.109959.short
4100  - http://molpharm.aspetjournals.org/content/early/2017/10/16/mol.117.109959.full
AB  - To better understand how adverse health effects are caused by particulate materials, and to develop preventative measures, it is important to identify the properties of particles and proteins that link exposure with specific biological outcomes. Coal fly ash (CFA) is a by-product of coal combustion that can affect human health. Here we show that human transient receptor potential melastatin-8 (TRPM8) and an N-terminally truncated TRPM8 variant (TRPM8-Δ801) are activated by CFA and calcium-rich nanoparticles and/or soluble salts within CFA. Human TRPM8 activation by CFA was potentiated by cold temperature and involved the phosphatidylinositol 4,5-bisphosphate binding site (L1008). Activation also occurred independent of the icilin and menthol binding site residue Y745, as well as to a large extent, the N-terminal amino acids 1-800. CFA, calcium nanoparticles and calcium salts also activated TRPV1 and TRPA1, but not TRPV4. Finally, CFA treatment caused CXCL1 and IL-8 mRNA induction in BEAS-2B and primary human bronchial epithelial cells through activation of both TRPM8 and TRPV1. However, neither mouse nor rat TRPM8 were activated by these materials, and Trpm8-knockout had no effect on cytokine induction in the lungs of mice following CFA instillation. These results imply that TRPM8, in conjunction with TRPV1 and TRPA1, might sense selected forms of inhaled particulate materials in human airways, shaping cellular responses to these materials. These findings improve our understanding of how and why certain particulate materials elicit different responses in biological systems, as well as ways in which certain particles might affect human health.