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Activation of TRPC cationic channels by mercurial compounds confers the cytotoxicity of mercury exposure

Xu, Shang-Zhong; Zeng, Bo; Atkin, Stephen L.; Daskoulidou, Nikoleta; Chen, Gui-Lan; Lukhele, Bhekithemba

Authors

Shang-Zhong Xu S.Xu@hull.ac.uk

Bo Zeng

Stephen L. Atkin

Nikoleta Daskoulidou

Gui-Lan Chen

Bhekithemba Lukhele



Abstract

Mercury is an established worldwide environmental pollutant with well-known toxicity affecting neurodevelopment in humans, but the molecular basis of cytotoxicity and the detoxification procedure are still unclear. Here we examined the involvement of the canonical transient receptor potential (TRPC) channel in the mercury-induced cytotoxicity and the potential detoxification strategy. Whole-cell and excised patches, Ca2+ imaging, and site-directed mutagenesis were used to determine the mechanism of action of mercurial compounds on TRPC channels overexpressed in HEK293 cells, and cytotoxicity and preventive effect were investigated in cell culture models using small interfering RNA and pharmacological blockers. Mercury potently activates TRPC4 and TRPC5 channels. The extracellular cysteine residues (C553 and C558) near the channel pore region of TRPC5 are the molecular targets for channel activation by mercury. The sensitivity of mercury to TRPC5 is presumed to be specific because other divalent heavy metal pollutants, such as Cd2+, Ni2+, and Zn2+, had no stimulating effect, and TRPC3, TRPC6, TRPV1, and TRPM2 were resistant to mercurial compounds. The channel activity of TRPC5, as well as TRPC4, induced by mercury, was prevented by 2-aminoethoxydiphenyl borate and modified by a reducing environment. The inhibition of TRPC5 channels by specific TRPC5 pore-blocking antibody or by SKF-96365 alleviated the cytotoxicity, whereas the mercury chelator, meso-2,3-dimercaptosuccinic acid, showed nonselective prevention of cell survival. Silencing of the TRPC5 gene reduced the mercury-induced neuronal damage. These results indicate that mercurial compounds are activators for TRPC5 and TRPC4 channels. Blockade of TRPC channels could be a novel strategy for preventing mercury-induced cytotoxicity and neurodevelopment impairment.

Journal Article Type Article
Publication Date 2012-01
Journal Toxicological Sciences
Print ISSN 1096-6080
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 125
Issue 1
Pages 56 - 68
APA6 Citation Xu, S., Zeng, B., Atkin, S. L., Daskoulidou, N., Chen, G., & Lukhele, B. (2012). Activation of TRPC cationic channels by mercurial compounds confers the cytotoxicity of mercury exposure. Toxicological Sciences, 125(1), 56 - 68. https://doi.org/10.1093/toxsci/kfr268
DOI https://doi.org/10.1093/toxsci/kfr268
Keywords Cationic channel; Calcium channel; TRPC; Mercury; Methylmercury; Dimercaptosuccinic acid; SKF-96365; 2-aminoethoxydiphenyl borate
Publisher URL https://academic.oup.com/toxsci/article/125/1/56/1668839


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