Lowered extracellular pH in a variety of tissues is associated with increased tissue destruction and initiation of inflammatory processes. While acid-sensing receptors described previously are ion channels, we describe a G-protein coupled proton-sensitive receptor that stimulates Ca²⁺ release from intracellular stores in a tumor-derived synoviocyte cell line (SW982) and in primary cultures of human synovial cells from patients with inflammatory arthropathies. We established a link between proton-dependent receptor activation and intracellular calcium mobilization by demonstrating (1) dependence on the integrity of the intracellular calcium store, (2) independence from extracellular calcium, and (3) proton-induced production of inositol phosphate; and (4) by abolishing the effect by GTP-ase inhibitors. We propose that this G-protein coupled acid-sensing receptor linked to intracellular Ca²⁺ mobilization in synoviocytes can contribute to downstream inflammatory and cellular proliferative processes in synovial fibroblasts. The acid-sensing receptor has distinct characteristics as a metabotropic G-protein coupled receptor on human synoviocytes in this emerging new class of receptors.