Journal
TOXINS
Volume 9, Issue 7, Pages -Publisher
MDPI AG
DOI: 10.3390/toxins9070227
Keywords
Buruli ulcer; mycolactone; AT(2) receptors; DRG neurons; membrane potential; image-based assay; high-content screening
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Funding
- European Community (ERC-STG INTRACELLTB Grant) [260901]
- European Community (MM4TB Grant) [260872]
- Agence Nationale de Recherche [ANR-10-EQPX-04-01, ANR-14-CE14-0024, ANR-14-CE08-0017, ANR-11-LABX-0015-01]
- Institut Pasteur of Lille
- FEDER [12001407]
- Region Nord-Pas-de-Calais [12000080]
- National Research Foundation (NRF) grant [2012R1A3A2048834, 2016M3A9B6021209]
- Korean government (MEST)
- Inserm Program ATIP avenir
- region Pays de la Loire (Kalmos project)
- Agence Nationale de la Recherche (ANR) [ANR-14-CE14-0024] Funding Source: Agence Nationale de la Recherche (ANR)
- National Research Foundation of Korea [2016M3A9B6021209, 2012R1A3A2048834] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- European Research Council (ERC) [260901] Funding Source: European Research Council (ERC)
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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 AT(2) receptors (angiotensin II type 2 receptors; AT(2)R), 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 AT(2)R, with this action being not affected by known ligands of AT(2)R. This result points towards novel AT(2)R-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.
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