Article ; Online: TRPM7 channels play a role in high glucose-induced endoplasmic reticulum stress and neuronal cell apoptosis.
The Journal of biological chemistry
2018 Volume 293, Issue 37, Page(s) 14393–14406
Abstract: ... endoplasmic reticulum stress (ERS) and injury of NS20Y neuronal cells. The cells were incubated in the absence or presence ... High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal ... of its kinase activity. Taken together, our findings suggest that TRPM7 channel activities play a key role in HG ...
| Abstract | High-glucose (HG) levels and hyperglycemia associated with diabetes are known to cause neuronal damage. The detailed molecular mechanisms, however, remain to be elucidated. Here, we investigated the role of transient receptor potential melastatin 7 (TRPM7) channels in HG-mediated endoplasmic reticulum stress (ERS) and injury of NS20Y neuronal cells. The cells were incubated in the absence or presence of HG for 48 h. We found that mRNA and protein levels of TRPM7 and of ERS-associated proteins, such as C/EBP homologous protein (CHOP), 78-kDa glucose-regulated protein (GRP78), and inducible nitric-oxide synthase (iNOS), increased in HG-treated cells, along with significantly increased TRPM7-associated currents in these cells. Similar results were obtained in cerebral cortical tissue from an insulin-deficiency model of diabetic mice. Moreover, HG treatment of cells activated ERS-associated proapoptotic caspase activity and induced cellular injury. Interestingly, a NOS inhibitor, l-NAME, suppressed the HG-induced increase of TRPM7 expression and cellular injury. siRNA-mediated TRPM7 knockdown or chemical inhibition of TRPM7 activity also suppressed HG-induced ERS and decreased cleaved caspase-12/caspase-3 levels and cell injury. Of note, TRPM7 overexpression increased ERS and cell injury independently of its kinase activity. Taken together, our findings suggest that TRPM7 channel activities play a key role in HG-associated ERS and cytotoxicity through an apoptosis-inducing signaling cascade involving HG, iNOS, TRPM7, ERS proteins, and caspases. |
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| MeSH term(s) | Animals ; Apoptosis/physiology ; Brain/metabolism ; Caspases/metabolism ; Diabetes Mellitus, Experimental/metabolism ; Endoplasmic Reticulum Stress/physiology ; Glucose/metabolism ; Heat-Shock Proteins/genetics ; Heat-Shock Proteins/metabolism ; Insulin/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/cytology ; Nitric Oxide Synthase Type II/genetics ; Nitric Oxide Synthase Type II/metabolism ; TRPM Cation Channels/genetics ; TRPM Cation Channels/metabolism ; TRPM Cation Channels/physiology ; Transcription Factor CHOP/genetics ; Transcription Factor CHOP/metabolism | |||||
| Chemical Substances | Ddit3 protein, mouse ; Heat-Shock Proteins ; Insulin ; TRPM Cation Channels ; Transcription Factor CHOP (147336-12-7) ; Nitric Oxide Synthase Type II (EC 1.14.13.39) ; Trpm7 protein, mouse (EC 2.7.1.-) ; Caspases (EC 3.4.22.-) ; Glucose (IY9XDZ35W2) ; molecular chaperone GRP78 (YCYIS6GADR) | |||||
| Language | English | |||||
| Publishing date | 2018-08-03 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2997-x | |||||
| ISSN | 1083-351X ; 0021-9258 | |||||
| ISSN (online) | 1083-351X | |||||
| ISSN | 0021-9258 | |||||
| DOI | 10.1074/jbc.RA117.001032 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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