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

FASEB J. 2011 Oct;25(10):3529-42. doi: 10.1096/fj.10-178483. Epub 2011 Jul 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate Ribose
  • Animals
  • Calcium / metabolism*
  • Calcium Signaling / physiology
  • Chemokines / pharmacology
  • Chemotaxis / physiology*
  • Dendritic Cells / cytology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / physiology*
  • Gene Expression Regulation / physiology
  • Inflammasomes / metabolism
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Lysosomes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • TRPM Cation Channels / metabolism*


  • Chemokines
  • Inflammasomes
  • Inositol 1,4,5-Trisphosphate Receptors
  • RNA, Messenger
  • RNA, Small Interfering
  • TRPM Cation Channels
  • TRPM2 protein, mouse
  • Adenosine Diphosphate Ribose
  • Calcium