The transient receptor potential X (TRP-X) is a non-selective cation channel implicated in physiological relevance.Here we show that TRP-X elevates intracellular Ca2+ concentration ([Ca2+]i) in dorsal root ganglion (DRG) neurons not only in the presence but also in the absence of extracellular Ca2+.Pharmacological and immunocytochemical analyses revealed the presence of TRP-X on both the plasma membrane and in a nonER organelle (nER).Confocal line-scan imaging demonstrated a close association of Ca2+ signals elicited by TRP-X activation with individual nER ("nER Ca2+ spark").In physiological solutions, the TRP-X mediated lysosomal Ca2+ release contributed to ～40％ of the overall [Ca2+]i rise and directly triggered vesicle exocytosis and neuropeptide release.The nER-localized TRP-X in DRG neurons also modulated TRP-X agonistinduced pain response and heat hyperalgesia in wild type but not TRP-X-deficient mice.Thus, in addition to working via Ca2+ influx, TRP-X triggers vesicle exocytosis in sensory neurons and modulates pain sensation by releasing Ca2+ from non-ER.