Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies
Neuropathic pain can develop as an agonizing sequela of diabetes mellitus and chronic uremia. A chemical link between both conditions of altered metabolism is the highly reactive compound methylglyoxal (MG), which accumulates in all cells, in particular neurons, and leaks into plasma as an index of...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
June 27, 2012
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| In: |
The journal of biological chemistry
Year: 2012, Volume: 287, Issue: 34, Pages: 28291-28306 |
| ISSN: | 1083-351X |
| DOI: | 10.1074/jbc.M111.328674 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1074/jbc.M111.328674 Verlag, Volltext: http://www.jbc.org/content/287/34/28291 
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| Author Notes: | Mirjam J. Eberhardt, Milos R. Filipovic, Andreas Leffler, Jeanne de la Roche, Katrin Kistner, Michael J. Fischer, Thomas Fleming, Katharina Zimmermann, Ivana Ivanovic-Burmazovic, Peter P. Nawroth, Angelika Bierhaus, Peter W. Reeh, and Susanne K. Sauer |
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| 245 | 1 | 0 | |a Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1) |b a possible mechanism of metabolic neuropathies |c Mirjam J. Eberhardt, Milos R. Filipovic, Andreas Leffler, Jeanne de la Roche, Katrin Kistner, Michael J. Fischer, Thomas Fleming, Katharina Zimmermann, Ivana Ivanovic-Burmazovic, Peter P. Nawroth, Angelika Bierhaus, Peter W. Reeh, and Susanne K. Sauer |
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| 520 | |a Neuropathic pain can develop as an agonizing sequela of diabetes mellitus and chronic uremia. A chemical link between both conditions of altered metabolism is the highly reactive compound methylglyoxal (MG), which accumulates in all cells, in particular neurons, and leaks into plasma as an index of the severity of the disorder. The electrophilic structure of this cytotoxic ketoaldehyde suggests TRPA1, a receptor channel deeply involved in inflammatory and neuropathic pain, as a molecular target. We demonstrate that extracellularly applied MG accesses specific intracellular binding sites of TRPA1, activating inward currents and calcium influx in transfected cells and sensory neurons, slowing conduction velocity in unmyelinated peripheral nerve fibers, and stimulating release of proinflammatory neuropeptides from and action potential firing in cutaneous nociceptors. Using a model peptide of the N terminus of human TRPA1, we demonstrate the formation of disulfide bonds based on MG-induced modification of cysteines as a novel mechanism. In conclusion, MG is proposed to be a candidate metabolite that causes neuropathic pain in metabolic disorders and thus is a promising target for medicinal chemistry. | ||
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