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Commentary highlighting valuable mechanistic insights provided by Klipp and Bankston on ASIC3 regulation by lipids.Acid-sensing ion channels (ASICs) are sensitized to activation by inflammatory mediators such as the polyunsaturated fatty acid (PUFA) arachidonic acid (AA). Previous work has shown that AA can potentiate ASIC currents at subsaturating proton concentrations, but the structural mechanisms of this change in gating are not understood. Here we show that PUFAs cause multiple gating changes in ASIC3, including shifting the pH dep