title: Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids.
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.
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Marra
authors.affiliation: CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Ferru-Clément
authors.affiliation: CHU-Nice, Hôpital l'Archet 1, Nice, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Breuil
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Delaunay
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Christin
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Friend
authors.affiliation: CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Sebille
authors.affiliation: CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Cognard
authors.affiliation: CNRS, Laboratoire de Signalisation et Transports Ioniques Membranaires (STIM), ERL 7368, Poitiers Cedex 9, France Université de Poitiers, ERL 7368, Poitiers Cedex 9, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Ferreira
authors.affiliation: CHU-Nice, Hôpital l'Archet 1, Nice, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Roux
authors.affiliation: CHU-Nice, Hôpital l'Archet 1, Nice, France.
authors.forename: Liana
authors.initials: L
authors.lastname: Euller-Ziegler
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Noel
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Lingueglia
authors.affiliation: CNRS, Institut de Pharmacologie Moléculaire et Cellulaire (IPMC), UMR 7275, Valbonne, France Université de Nice Sophia Antipolis, UMR 7275, Valbonne, France LabEx Ion Channel Science and Therapeutics, Valbonne, France deval@ipmc.cnrs.fr.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Deval
mesh_terms: D062565:Acid Sensing Ion Channels / Q000096:biosynthesis*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002460:Cell Line; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D018345:Mice, Knockout; D009619:Nociceptors / Q000502:physiology*; D010146:Pain; D051381:Rats
chemical_list: C112231:ASIC3 protein, human; D062565:Acid Sensing Ion Channels; D008244:Lysophosphatidylcholines; D016718:Arachidonic Acid
keywords: acid‐sensing ion channels; arachidonic acid; lysophosphatidylcholine; pain; sodium channels