Zinc-induced neurotoxicity mediated by transient receptor potential melastatin 7 channels.
Transient receptor potential melastatin 7 (TRPM7) channels are novel Ca(2+)-permeable non-selective cation channels ubiquitously expressed. Activation of TRPM7 channels has been shown to be involved in cellular Mg(2+) homeostasis, diseases caused by abnormal magnesium absorption, and in Ca(2+)-mediated neuronal injury under ischemic conditions. Here we show strong evidence suggesting that TRPM7 channels also play an important role in cellular Zn(2+) homeostasis and in Zn(2+)-mediated neuronal injury. Using a combination of fluorescent Zn(2+) imaging, small interfering RNA, pharmacological analysis, and cell injury assays, we show that activation of TRPM7 channels augmented Zn(2+)-induced injury of cultured mouse cortical neurons. The Zn(2+)-mediated neurotoxicity was inhibited by nonspecific TRPM7 blockers Gd(3+) or 2-aminoethoxydiphenyl borate, and by knockdown of TRPM7 channels with small interfering RNA. In addition, Zn(2+)-mediated neuronal injury under oxygen-glucose deprivation conditions was also diminished by silencing TRPM7. Furthermore, we show that overexpression of TRPM7 channels in HEK293 cells increased intracellular Zn(2+) accumulation and Zn(2+)-induced cell injury, while silencing TRPM7 by small interfering RNA attenuated the Zn(2+)-mediated cell toxicity. Thus, TRPM7 channels may represent a novel target for neurological disorders where Zn(2+) toxicity plays an important role.
Inoue
Koichi
K
Robert S Dow Neurobiology Laboratories, Legacy Research, Portland, Oregon 97232, USA.
Branigan
Deborah
D
Xiong
Zhi-Gang
ZG
D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism; D018408:Patch-Clamp Techniques; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*
D009498:Neurotoxins; D034741:RNA, Small Interfering; D050053:TRPM Cation Channels; C421903:Trpm7 protein, mouse; D008274:Magnesium; D005947:Glucose; D015032:Zinc; D010100:Oxygen; D002118:Calcium