Intracellular TRPA1 mediates Ca(2+) 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 Ca(2+) concentration ([Ca(2+)](i)) in dorsal root ganglion (DRG) neurons in the presence and absence of extracellular Ca(2+). Pharmacological and immunocytochemical analyses revealed the presence of TRPA1 channels both on the plasma membrane and in endolysosomes. Confocal line-scan imaging demonstrated Ca(2+) signals elicited from individual endolysosomes (“lysosome Ca(2+) sparks”) by TRPA1 activation. In physiological solutions, the TRPA1-mediated endolysosomal Ca(2+) release contributed to ∼40% of the overall [Ca(2+)](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 Ca(2+) influx, TRPA1 channels trigger vesicle release in sensory neurons by releasing Ca(2+) from lysosome-like organelles.