Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells

Abstract

To better understand how adverse health effects are caused by exposure to particulate materials, and to develop preventative measures, it is important to identify the properties of particles and molecular targets that link exposure with specific biologic outcomes. Coal fly ash (CFA) is a by-product of coal combustion that can affect human health. We report 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. TRPM8 activation by CFA was potentiated by cold temperature involving the phosphatidylinositol 4,5-bisphosphate binding residue (L1008), but was independent of the icilin and menthol binding site residue Y745 and, essentially, the N-terminal amino acids 1-800. CFA, calcium nanoparticles, and calcium salts also activated transient receptor potential vanilloid-1 (TRPV1) and transient receptor potential ankyrin-1 (TRPA1), but not TRPV4. CFA treatment induced CXCL1 and interleukin-8 mRNA in BEAS-2B and primary human bronchial epithelial cells through activation of both TRPM8 and TRPV1. However, neither mouse nor rat TRPM8 was activated by these materials, and knockout had no effect on cytokine induction in the lungs of CFA-instilled mice. Amino acids S921 and S927 in mouse were identified as important for the lack of response to CFA. 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, and improving our understanding of how and why certain particulate materials elicit different responses in biologic systems, affecting human health.

trans-Anethole of Fennel Oil is a Selective and Nonelectrophilic Agonist of the TRPA1 Ion Channel

“…Calcium imaging of transiently transfected HEK-GCaMP6overexpressing cells was also performed as described previously (Deering-Rice et al, 2011Lamb et al, 2017). In brief, HEK-GCaMP6 cells were transfected prior to studies as described earlier.…”

TRP Channels as Cellular Targets of Particulate Matter

“…Exposure to coal fly ash (CFA) induces pro-apoptotic and pro-inflammatory reactions and leads to pulmonary injury by altering the expression of endoplasmic reticulum stress-associated genes. In addition it triggers the cough reflex, suppressing the respiratory rate and stimulating neurogenic edema [ 92 , 94 ]. CFA particles are mineral-rich particles of 50 nm to 150 μm diameter composed mostly from silicon, aluminum, calcium, iron oxides and carbon.…”

“…CFA particles are mineral-rich particles of 50 nm to 150 μm diameter composed mostly from silicon, aluminum, calcium, iron oxides and carbon. It activates TRPM8, TRPV1 and TRPA1 (in the order of their activation susceptibility), but not TRPM2, TRPV2, TRPV3 and TRPV4 [ 8 , 51 , 94 , 95 , 96 ]. When three of the intracellular amino acids of TRPA1 channel are mutated, CFA has the ability to exert a greater effect on R3C, R58T (N-terminus) and H1018R (C-terminus) variants.…”

“…In contrast, DEP and crystalline silica do not significantly activate the channel. TRPM8 has the greatest affinity for CFA1, followed by TRPV1 and TRPA1 [ 94 ].…”

Peculiarities of Trpm8 Receptor Expression in the Respiratory Tract of Asthma Patients

“…Катионный канал с транзиторным рецепторным потенциалом меластатинового подсемейства 8 (TRPM8) известен как холодовой рецептор, активный в диапазоне температур 8-28ºC [11]. Однако помимо чувствительности к температуре, как и прочие TRP каналы, TRPM8 характеризуется чувствительностью ко многим другим физическим и химическим стимулам, таким как повышенное осмотическое давление [13], pH [3], пылевые частицы [6], сигаретный дым и продукты оксидативного стресса [8], а также тестостерон [1]. Вероятно, что некоторые из активирующих стимулов остаются не описанными до сих пор.…”