title: Methylglyoxal activates nociceptors through transient receptor potential channel A1 (TRPA1): a possible mechanism of metabolic neuropathies.
abstract: 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.
authors: Institute of Physiology and Pathophysiology Friedrich-Alexander University Erlangen-Nuremberg, Universitaetsstrasse 17, 91054 Erlangen, Germany.
authors: Mirjam J
authors: MJ
authors: Eberhardt
authors: Milos R
authors: MR
authors: Filipovic
authors: Andreas
authors: A
authors: Leffler
authors: Jeanne
authors: J
authors: de la Roche
authors: Katrin
authors: K
authors: Kistner
authors: Michael J
authors: MJ
authors: Fischer
authors: Thomas
authors: T
authors: Fleming
authors: Katharina
authors: K
authors: Zimmermann
authors: Ivana
authors: I
authors: Ivanovic-Burmazovic
authors: Peter P
authors: PP
authors: Nawroth
authors: Angelika
authors: A
authors: Bierhaus
authors: Peter W
authors: PW
authors: Reeh
authors: Susanne K
authors: SK
authors: Sauer
mesh_terms: D000200:Action Potentials; D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000178:diet therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000378:metabolism; D009619:Nociceptors / Q000378:metabolism* / Q000473:pathology; D011765:Pyruvaldehyde / Q000378:metabolism*; D051381:Rats; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D015220:Calcium Channels; D018836:Inflammation Mediators; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C480976:Trpa1 protein, rat; D011765:Pyruvaldehyde