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An Environmental Pollutant, 9,10-phenanthrenequinone, Activates Human TRPA1 via Critical Cysteines 621 and 665

An Environmental Pollutant, 9,10-phenanthrenequinone, Activates Human TRPA1 via Critical Cysteines 621 and 665

Katsuhiko Muraki, Takashi Sekine, Yuna Ando, Hiroka Suzuki, Noriyuki Hatano, Tadashi Hirata, Yukiko Muraki

Pharmacol Res Perspect. 2017 Aug;5(4):e00342.

PMID: 28805980

Abstract:

Transient receptor potential ankyrin 1 (TRPA1) is activated by noxious cold, mechanical stimulation, and irritant chemicals. In our recent study, 9, 10-phenanthrenequinone (9,10-PQ) is the most potent irritant for activation of NRF2 among 1395 cigarette smoke components and it may be, therefore, important to find its additional targets. Here, we show that 9,10-PQ functions as an activator of TRPA1 in human embryonic kidney (HEK) cells expressing human wild-type TRPA1 (HEK-wTRPA1) and human alveolar A549 (A549) cells. Application of 9,10-PQ at 0.1-10 μmol/L induced a concentration-dependent Ca2+ response as well as inward currents at -50 mV in HEK-wTRPA1 cells. The current response was blocked by TRPA1 antagonists, HC-030031 (HC) and A-967079. To test whether 9,10-PQ affects the cysteine residues of TRPA1, we expressed mutant TRPA1 channels in HEK cells (HEK-muTRPA1) in which six different cysteine residues were replaced with serine. Among them, a mutation of cysteine 621 (C621S) abolished the 9,10-PQ-induced Ca2+ and current responses. The channel activity induced by 9,10-PQ was also abolished in excised inside-out patches isolated from HEK-muTRPA1 cells with the C621S substitution. Although a mutation of cysteine 665 (C665S) reduced the 9,10-PQ-induced response, channel sensitization by pretreatment with Cu2+ plus 1,10-phenanthroline and by internal dialysis of 3 μmol/L Ca2+ restored the response. However, a double mutant with C621S and C665S substitutions had little response to 9,10-PQ, even when sensitized by Ca2+ dialysis. In A549 cells, 9,10-PQ induced an HC-sensitive Ca2+ response. Our findings demonstrate that 9,10-PQ activation of human TRA1 is dependent on cysteine residues 621 and 665.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP84117	9,10-Phenanthrenequinone		84-11-7	Price

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