-Gingerol, a major phenolic compound derived from ginger (Zingiber officinale), is a potential chemopreventive compound that can induce stress in cancer cells and cause apoptotic cell death. This study examines the early signaling effects of -gingerol on renal cells. It was found that -gingerol caused a slow and sustained rise of [Ca2+]i in a concentration-dependent manner. -Gingerol also induced a [Ca2+]i rise when extracellular Ca2+ was removed, but the magnitude was reduced by 80%. Depletion of intracellular Ca2+ stores with CCCP, a mitochondrial uncoupler, did not affect the action of -gingerol. In a Ca2+-free medium, the -gingerol-induced [Ca2+]i rise was partially abolished by depleting stored Ca2+ with thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor). The elevation of -Gingerol-caused [Ca2+]i in a Ca2+-containing medium was not affected by modulation of protein kinase C activity. The -gingerol-induced Ca2+ influx was blocked by nicardipine. U73122, an inhibitor of phospholipase C, abolished ATP (but not -gingerol)-induced [Ca2+]i rise. These findings suggest that -gingerol induces a significant rise in [Ca2+]i in MDCK renal tubular cells by stimulating both extracellular Ca2+ influx and thapsigargin-sensitive intracellular Ca2+ release via as yet unidentified mechanisms.