A schematic of the role of acid-sensing ion channel (ASIC)1 and ASIC3 involved in synoviocyte function under normal and inflammatory conditions. (A) This diagram shows fibroblast-like synoviocytes (FLS) under normal non inflamed conditions. Extracellular protons (H+, acidic pH) activate the ASIC3 and ASIC1 that increase calcium release from intracellular stores. The increases in intracellular calcium through ASIC3 activate protein phosphatase 2A (PP2A) which subsequently dephosphorylates extracellular signal-regulated kinase (ERK). This reduction in phosphorylation of ERK counteracts the increases in intracellular calcium so that there is no cell death of FLS. (B) Under inflammatory conditions, FLS are exposed to inflammatory mediators, such as IL-1β as well as an acidic environment. The combination of these two factors results an enhanced response and cell death. IL-1β increases expression of ASIC3 and decreases expression of ASIC1 results in ion channels with a greater proportion of ASIC3 on FLS to sense the increased protons from the acidic environment. Activation of ASIC3 by protons would then result in enhanced calcium release intracellularly. IL-1β by itself can modulate calcium and can enhance phosphorylation of ERK. This enhanced intracellular calcium by activation of ASIC3 and IL-1β, along with enhanced phosphorylation of p-ERK by activation of IL-1β receptor activation shifts the balance of calcium and p-ERK to favor cell death. Thus, under inflammatory conditions, decreases in pH activate ASIC3 to produce cell death.