Journal
EMBO JOURNAL
Volume 35, Issue 4, Pages 414-428Publisher
WILEY
DOI: 10.15252/embj.201592335
Keywords
acid-sensing ion channels; arachidonic acid; lysophosphatidylcholine; pain; sodium channels
Categories
Funding
- Fondation pour la Recherche Medicale [DEQ20110421309]
- Agence Nationale de la Recherche [ANR-13-BSV4-0009]
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV4-0009] Funding Source: Agence Nationale de la Recherche (ANR)
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Extracellular pH variations are seen as the principal endogenous signal that triggers activation of Acid-Sensing Ion Channels (ASICs), which are basically considered as proton sensors, and are involved in various processes associated with tissue acidification. Here, we show that human painful inflammatory exudates, displaying nonacidic pH, induce a slow constitutive activation of human ASIC3 channels. This effect is largely driven by lipids, and we identify lysophosphatidylcholine (LPC) and arachidonic acid (AA) as endogenous activators of ASIC3 in the absence of any extracellular acidification. The combination of LPC and AA evokes robust depolarizing current in DRG neurons at physiological pH 7.4, increases nociceptive C-fiber firing, and induces pain behavior in rats, effects that are all prevented by ASIC3 blockers. Lipid-induced pain is also significantly reduced in ASIC3 knockout mice. These findings open new perspectives on the roles of ASIC3 in the absence of tissue pH variation, as well as on the contribution of those channels to lipid-mediated signaling.
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