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Toxins (Basel). 2017 Jul 18;9(7). pii: E227. doi: 10.3390/toxins9070227.

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

Author information

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. ok-ryul.song@ibl.cnrs.fr.
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. u4588719@snu.ac.kr.
3
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. samuel.jouny@inserm.fr.
4
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. isabelle.ricard@ibl.cnrs.fr.
5
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. alexandre.vandeputte@ibl.cnrs.fr.
6
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. nathalie.deboosere@pasteur-lille.fr.
7
Equipe ATIP AVENIR, CRCINA, INSERM, Université de Nantes, Université d'Angers, 4 rue Larrey, F-49933 Angers, France. estelle.marion@inserm.fr.
8
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. cj.queval@gmail.com.
9
Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France; CNRS UMR5203, Montpellier, France. pierre.Lesport@igf.cnrs.fr.
10
Laboratories of Excellence, Ion Channel Science and Therapeutics, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, 34094 Montpellier, France; CNRS UMR5203, Montpellier, France. emmanuel.Bourinet@igf.cnrs.fr.
11
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. daniel.henrion@univ-angers.fr.
12
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. odolbae@snu.ac.kr.
13
INSERM U1191, CNRS UMR 5203, Institut de Génomique Fonctionnelle, 141 rue de la Cardonille, F-34094 Montpellier, France. guillaume.Lebon@igf.cnrs.fr.
14
Laboratories of Excellence, Ion Channel Science and Therapeutics, UMR 7277, Institute of Biology Valrose (iBV), Université Nice Sophia Antipolis, F-06100 Nice, France. guillaume.sandoz@unice.fr.
15
Unité de Microbiologie Structurale, CNRS UMR3528 Institut Pasteur, 75015 Paris, France. edouard.yeramian@pasteur.fr.
16
Equipe ATIP AVENIR, CRCINA, INSERM, Université de Nantes, Université d'Angers, 4 rue Larrey, F-49933 Angers, France. laurent.marsollier@inserm.fr.
17
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France. priscille.brodin@inserm.fr.

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.

KEYWORDS:

AT2 receptors; Buruli ulcer; DRG neurons; high-content screening; image-based assay; membrane potential; mycolactone

PMID:
28718822
PMCID:
PMC5535174
DOI:
10.3390/toxins9070227
[Indexed for MEDLINE]
Free PMC Article

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