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Toxins 2017, 9(7), 227; doi:10.3390/toxins9070227

A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone

1
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
2
Pain Cognitive Function Research Center, Department of Brain and Cognitive Sciences College of Natural Sciences, Dental Research Institute and Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul 110-799, Korea
3
CRCINA, INSERM, Université de Nantes, Université d’Angers, 4 rue Larrey, F-49933 Angers, France
4
Equipe ATIP AVENIR, CRCINA, INSERM, Université de Nantes, Université d’Angers, 4 rue Larrey, F-49933 Angers, France
5
Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France
6
CNRS UMR5203, 141 rue de la Cardonille, 34094 Montpellier, France
7
INSERM U1191, Univ. Montpellier, 141 rue de la Cardonille, 34094 Montpellier, France
8
UMR CNRS 6214-INSERM 1083, Laboratoire de Biologie Neurovasculaire et Mitochondriale Intégrée, UFR Sciences Médicales, Université d’Angers, Rue Haute de Reculée, 49045 Angers, France
9
INSERM U1191, CNRS UMR 5203, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, F-34094 Montpellier, France
10
Laboratories of Excellence, Ion Channel Science and Therapeutics, UMR 7277, Institute of Biology Valrose (iBV), Université Nice Sophia Antipolis, F-06100 Nice, France
11
Unité de Microbiologie Structurale, CNRS UMR3528 Institut Pasteur, 75015 Paris, France
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Flaminia Pavone
Received: 21 May 2017 / Revised: 10 July 2017 / Accepted: 13 July 2017 / Published: 18 July 2017
(This article belongs to the Section Bacterial Toxins)
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Abstract

Mycolactone, a polyketide molecule produced by Mycobacterium ulcerans, is the etiological agent of Buruli ulcer. This lipid toxin is endowed with pleiotropic effects, presents cytotoxic effects at high doses, and notably plays a pivotal role in host response upon colonization by the bacillus. Most remarkably, mycolactone displays intriguing analgesic capabilities: the toxin suppresses or alleviates the pain of the skin lesions it inflicts. We demonstrated that the analgesic capability of mycolactone was not attributable to nerve damage, but instead resulted from the triggering of a cellular pathway targeting AT2 receptors (angiotensin II type 2 receptors; AT2R), and leading to potassium-dependent hyperpolarization. This demonstration paves the way to new nature-inspired analgesic protocols. In this direction, we assess here the hyperpolarizing properties of mycolactone on nociceptive neurons. We developed a dedicated medium-throughput assay based on membrane potential changes, and visualized by confocal microscopy of bis-oxonol-loaded Dorsal Root Ganglion (DRG) neurons. We demonstrate that mycolactone at non-cytotoxic doses triggers the hyperpolarization of DRG neurons through AT2R, with this action being not affected by known ligands of AT2R. This result points towards novel AT2R-dependent signaling pathways in DRG neurons underlying the analgesic effect of mycolactone, with the perspective for the development of new types of nature-inspired analgesics. View Full-Text
Keywords: Buruli ulcer; mycolactone; AT2 receptors; DRG neurons; membrane potential; image-based assay; high-content screening Buruli ulcer; mycolactone; AT2 receptors; DRG neurons; membrane potential; image-based assay; high-content screening
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Song, O.-R.; Kim, H.-B.; Jouny, S.; Ricard, I.; Vandeputte, A.; Deboosere, N.; Marion, E.; Queval, C.J.; Lesport, P.; Bourinet, E.; Henrion, D.; Oh, S.B.; Lebon, G.; Sandoz, G.; Yeramian, E.; Marsollier, L.; Brodin, P. A Bacterial Toxin with Analgesic Properties: Hyperpolarization of DRG Neurons by Mycolactone. Toxins 2017, 9, 227.

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