Referenced in: none

Automatically associated channels: TRP , TRPM , TRPM2

Title: Dendritic cell maturation and chemotaxis is regulated by TRPM2-mediated lysosomal Ca2+ release.

Authors: Adriana Sumoza-Toledo, Ingo Lange, Hanna Cortado, Harivadan Bhagat, Yasuo Mori, Andrea Fleig, Reinhold Penner, Santiago Partida-Sánchez

Journal, date & volume: FASEB J., 2011 Oct , 25, 3529-42

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/21753080

Abstract
Chemokines induce calcium (Ca(2+)) signaling and chemotaxis in dendritic cells (DCs), but the molecular players involved in shaping intracellular Ca(2+) changes remain to be characterized. Using siRNA and knockout mice, we show that in addition to inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release and store-operated Ca(2+) entry (SOCE), the transient receptor potential melastatin 2 (TRPM2) channel contributes to Ca(2+) release but not Ca(2+) influx in mouse DCs. Consistent with these findings, TRPM2 expression in DCs is restricted to endolysosomal vesicles, whereas in neutrophils, the channel localizes to the plasma membrane. TRPM2-deficient DCs show impaired maturation and severely compromised chemokine-activated directional migration as well as bacterial-induced DC trafficking to the draining lymph nodes. Defective DC chemotaxis is due to perturbed chemokine-receptor-initiated Ca(2+) signaling mechanisms, which include suppression of TRPM2-mediated Ca(2+) release and secondary modification of SOCE. DCs deficient in both TRPM2 and IP(3) receptor signaling lose their ability to perform chemotaxis entirely. These results highlight TRPM2 as a key player regulating DC chemotaxis through its function as Ca(2+) release channel and confirm ADP-ribose as a novel second messenger for intracellular Ca(2+) mobilization.