Intracellular trpa1 mediates ca²⁺ release from lysosomes in dorsal root ganglion neurons

Transient receptor potential A1 (TRPA1) is a nonselective cation channel implicated in thermosensation and inflammatory pain. In this study, we show that TRPA1 (activated by allyl isothiocyanate, acrolein, and 4-hydroxynonenal) elevates the intracellular Ca²⁺ concentration ([Ca²⁺]i) in dorsal root ganglion (DRG) neurons in the presence and absence of extracellular Ca²⁺. Pharmacological and immunocytochemical analyses revealed the presence of TRPA1 channels both on the plasma membrane and in endolysosomes. Confocal line-scan imaging demonstrated Ca²⁺ signals elicited from individual endolysosomes ("lysosome Ca²⁺ sparks") by TRPA1 activation. In physiological solutions, the TRPA1- mediated endolysosomal Ca²⁺ release contributed to ~40% of the overall [Ca²⁺]i rise and directly triggered vesicle exocytosis and calcitonin gene-related peptide release, which greatly enhanced the excitability of DRG neurons. Thus, in addition to working via Ca²⁺ influx, TRPA1 channels trigger vesicle release in sensory neurons by releasing Ca²⁺ from lysosome-like organelles.