Methylglyoxal Activates Nociceptors through Transient Receptor Potential Channel A1 (TRPA1): A POSSIBLE MECHANISM OF METABOLIC NEUROPATHIES

Mirjam J. Eberhardt,Ivana Ivanovic-Burmazovic,Katrin Kistner,Milos R. Filipovic,Angelika Bierhaus,Andreas Leffler,Susanne K. Sauer,Jeanne de la Roche,Michael J. Fischer,Peter W. Reeh,Thomas Fleming,Katharina Zimmermann,Peter P. Nawroth

doi:10.1074/jbc.m111.328674

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.

Highlights

Methylglyoxal is a reactive metabolite that modifies proteins and accumulates in diabetes and uremia
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
Methylglyoxal Activates Human TRPA1—To investigate whether MG exhibits TRPA1 agonistic properties, HEK 293t cells expressing wild type human TRPA1 (hTRPA1) were examined by standard whole-cell voltage clamp

Summary

Introduction

Methylglyoxal is a reactive metabolite that modifies proteins and accumulates in diabetes and uremia. Results: Methylglyoxal excites nociceptors and releases neuropeptides via activation of TRPA1 channels by modifying their intracellular N-terminal cysteine and lysine residues. Conclusion: Methylglyoxal acting through TRPA1 is a possible cause of painful metabolic neuropathies. Significance: Methylglyoxal and its reaction with TRPA1 are promising targets for medicinal chemistry to fight neurotoxicity. 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. MG is proposed to be a candidate metabolite that causes neuropathic pain in metabolic disorders and is a promising target for medicinal chemistry

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Conclusion