Editors' ChoiceNeuroscience

Pain in the joint

Sci. Signal.  01 Mar 2016:
Vol. 9, Issue 417, pp. ec43
DOI: 10.1126/scisignal.aaf5488

Acid-sensing ion channels (ASICs) are sodium channels that are, as their name implies, gated by extracellular protons. ASICs are present in neurons throughout the central and peripheral nervous systems and have been implicated in several processes, including nociception. Marra et al. found that certain lipids can also activate these channels. Despite having a physiologically neutral pH of 7.4, inflammatory exudates collected from patients with painful, swollen knee joints stimulated an inward current in HEK293T cells expressing human ASIC3 but not in cells expressing human ASIC1a. Depleting the exudates of lipids before applying them to the cells or treating the cells with exudates plus APETx2, a peptide toxin that specifically inhibits ASIC3, prevented exudate-induced currents. After using gas chromatography and mass spectrometry to identify and quantify the lipids present in the inflammatory exudates, the authors individually tested several lipids for the ability to activate ASIC3. Application of purified arachidonic acid (AA) or various species of lysophosphatidylcholine (LPC) induced sustained ASIC3-mediated currents at neutral pH. AA and LPC are produced by hydrolysis of phosphatidylcholine by phospholipase A2 (PLA2), an enzyme that is secreted by most mammalian cells and thus is present in most tissues. Coapplication of both AA and LPC more strongly stimulated ASIC3-mediated current in ASIC3-expressing cultured cells than did either lipid alone. Coapplication of both AA and LPC induced currents in neurons isolated from rat dorsal root ganglia and stimulated action potentials in isolated rat hindpaw saphenous nerves. Last, injecting AA plus LPC into the rat hindpaw induced pain responses, which were reduced when APETx2 was coinjected with the lipids. Compared with samples from control subjects, synovial fluid from rheumatoid arthritis patients has increased LPC, suggesting that lipid-mediated activation of ASIC3 may be one of the reasons swollen joints are so painful.

S. Marra, R. Ferru-Clément, V. Breuil, A. Delaunay, M. Christin, V. Friend, S. Sebille, C. Cognard, T. Ferreira, C. Roux, L. Euller-Ziegler, J. Noel, E. Lingueglia, E. Deval, Non-acidic activation of pain-related Acid-Sensing Ion Channel 3 by lipids. EMBO J. 35, 414–428 (2016). [PubMed]

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