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

Shang Zhong Xu, Bo Zeng, Nikoleta Daskoulidou, Gui Lan Chen, Stephen Atkin, Bhekithemba Lukhele

Research output: Contribution to journalArticle

26 Citations (Scopus)

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, Ca 2+ 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 (C 553 and C 558) 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 Cd 2+, Ni 2+, and Zn 2+, 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.

Original languageEnglish
Article numberkfr268
Pages (from-to)56-68
Number of pages13
JournalToxicological Sciences
Volume125
Issue number1
DOIs
Publication statusPublished - 2012
Externally publishedYes

Fingerprint

Cytotoxicity
Mercury
Chemical activation
Detoxification
1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole
Succimer
Transient Receptor Potential Channels
Environmental Pollutants
Mutagenesis
Blocking Antibodies
HEK293 Cells
Gene Silencing
Chelating Agents
Heavy Metals
Site-Directed Mutagenesis
Cell culture
Small Interfering RNA
Cysteine
Toxicity
Cell Survival

Keywords

  • 2-aminoethoxydiphenyl borate
  • Calcium channel
  • Cationic channel
  • Dimercaptosuccinic acid
  • Mercury
  • Methylmercury
  • SKF-96365
  • TRPC

ASJC Scopus subject areas

  • Toxicology

Cite this

Activation of TRPC cationic channels by mercurial compounds confers the cytotoxicity of mercury exposure. / Xu, Shang Zhong; Zeng, Bo; Daskoulidou, Nikoleta; Chen, Gui Lan; Atkin, Stephen; Lukhele, Bhekithemba.

In: Toxicological Sciences, Vol. 125, No. 1, kfr268, 2012, p. 56-68.

Research output: Contribution to journalArticle

Xu, Shang Zhong ; Zeng, Bo ; Daskoulidou, Nikoleta ; Chen, Gui Lan ; Atkin, Stephen ; Lukhele, Bhekithemba. / Activation of TRPC cationic channels by mercurial compounds confers the cytotoxicity of mercury exposure. In: Toxicological Sciences. 2012 ; Vol. 125, No. 1. pp. 56-68.
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AU - Atkin, Stephen

AU - Lukhele, Bhekithemba

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AB - 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, Ca 2+ 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 (C 553 and C 558) 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 Cd 2+, Ni 2+, and Zn 2+, 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.

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KW - Methylmercury

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