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Acid-sensing ion channels (ASICs) are proton-gated cation channels and are emerging as key sensors for extracellular protons in central and peripheral neurons.The currents mediated by ASICs inactivate rapidly even in the continuous presence of agonist (protons).Remarkably, type 3 ASIC (ASIC3), which is predominantly distributed in sensory neurons, responds to mild acidosis (pH 6.8-7.2) with a sustained current.This characteristics has been proposed to mediate persistent acidic pain associated with arthritis, muscular ischemia, and cancer.In the present study, we investigated acute modulation of ASIC3-containing channels by various inflammatory mediators in both dorsal root ganglia (DRG) neurons and CHO ceils expressing ASIC subunits.We found that serotonin (5-HT), a classical proinflammatory mediator, specifically enhanced the sustained currents of homomeric ASIC3 and heteromeric ASIC3/lb channels.Mechanistically, 5-HT directly acts on ASIC3 channels rather than through 5-HT receptors, because specific receptor antagonists did not affect 5-HT enhancement.More importantly, mutations at ASIC3 (E79A, E79S, E423A and Q269A) completely abolished 5-HT-induced enhancement.Moreover, co-application of 5-HT and acetic acid significantly increased pain-related behaviors as assayed in the paw-licking test in mice, which was largely attenuated in ASIC3-deletion mice and inhibited by the nonselective ASICs inhibitor amiloride but not by 5-HT receptor antagonists methysergide and Y-25130.Taken together, these data identify ASIC3 channels as a molecular target for rapid actions of 5-HT and reinforce the importance of ASIC3 channels in regulating inflammatory pain.