Transient Receptor Potential Melastatin 2 (TRPM2) is a Calcium Release Channel Essential for Chemotaxis of Dendritic Cells (44.17)

Abstract

Abstract Chemokines induce Ca2+ signaling and chemotaxis in dendritic cells (DCs) but the molecular players involved in shaping the changes in intracellular Ca2+ remain to be characterized. Using siRNA and knock-out mice, we show that in addition to IP3-mediated Ca2+ release and store-operated Ca2+ entry the transient receptor potential melastatin 2 (TRPM2) channel contributes to Ca2+ release, but not Ca2+ influx in mouse DCs. Consistent with this observation, TRPM2 expression in DCs cells is restricted to endolysosomal vesicles, whereas in neutrophils the channel localizes to the plasma membrane and does not participate in Ca2+ release. While TRPM2 is not involved in DCs maturation, TRPM2-deficient DCs show severely compromised chemotaxis regardless of maturation stage. This is due to perturbed Ca2+ signaling manifested through suppression of specific TRPM2-mediated Ca2+-release events and an additional secondary modification of store-operated Ca2+ entry. DCs deficient in both TRPM2 and inositol-1,4,5-trisphosphate receptor signaling (InsP3R) lose their ability to perform chemotaxis entirely. These findings confirm ADPR as a novel second messenger and highlight TRPM2 as a key player regulating DCs chemotaxis through its function as Ca2+ release channel.