Non‐acidic activation of pain‐related Acid‐Sensing Ion Channel 3 by lipids. (15th January 2016)

• Record Type: Journal Article
• Authors: Marra, Sébastien; Ferru‐Clément, Romain; Breuil, Véronique; Delaunay, Anne; Christin, Marine; Friend, Valérie; Sebille, Stéphane; Cognard, Christian; Ferreira, Thierry; Roux, Christian; Euller‐Ziegler, Liana; Noel, Jacques; Lingueglia, Eric; Deval, Emmanuel
• Is Part Of: EMBO journal. Volume 35:Number 4(2016)
• Page Start: 414
• Page End: 428
• Publication Date: 2016-01-15
• Subjects: acid‐sensing ion channels -- arachidonic acid -- lysophosphatidylcholine -- pain -- sodium channels; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201592335
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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 non‐acidic 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. Synopsis: ASIC3 is a proton‐sensitive ion channel linked to pain perception. The finding that certain lipids activate ASIC3 in the absence of tissue acidification challenges our view of pain‐causing agents and suggests crosstalk between pH fluctuations and lipid signaling. Non‐acidic joint effusions from patients with pain constitutively activate ASIC3. The effect is lipid‐dependent and exudates contain high levels of lysophosphatidylcholine (LPC) and arachidonic acid (AA). LPC and AA are primarily responsible for ASIC3 activation at resting pH 7.4. LPC and AA evoke ASIC3‐dependent pain behaviour in rodents. Abstract : ASIC3 is a proton‐sensitive ion channel linked to pain perception. The finding that certain lipids activate ASIC3 in the absence of tissue acidification challenges our view of pain‐causing agents and suggests crosstalk between pH fluctuations and lipid signaling.