NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist.
The nucleotide NAADP was recently discovered as a second messenger involved in the initiation and propagation of Ca(2+) signaling in lymphoma T cells, but its impact on primary T cell function is still unknown. An optimized, synthetic, small molecule inhibitor of NAADP action, termed BZ194, was designed and synthesized. BZ194 neither interfered with Ca(2+) mobilization by d-myo-inositol 1,4,5-trisphosphate or cyclic ADP-ribose nor with capacitative Ca(2+) entry. BZ194 specifically and effectively blocked NAADP-stimulated [(3)H]ryanodine binding to the purified type 1 ryanodine receptor. Further, in intact T cells, Ca(2+) mobilization evoked by NAADP or by formation of the immunological synapse between primary effector T cells and astrocytes was inhibited by BZ194. Downstream events of Ca(2+) mobilization, such as nuclear translocation of "nuclear factor of activated T cells" (NFAT), T cell receptor-driven interleukin-2 production, and proliferation in antigen-experienced CD4(+) effector T cells, were attenuated by the NAADP antagonist. Taken together, specific inhibition of the NAADP signaling pathway constitutes a way to specifically and effectively modulate T-cell activation and has potential in the therapy of autoimmune diseases.
Dammermann
Werner
W
The Calcium Signaling Group, University Medical Centre Hamburg-Eppendorf, Centre of Experimental Medicine, Institute of Biochemistry and Molecular Biology I Cellular Signal Transduction, 20246 Hamburg, Germany.
Zhang
Bo
B
Nebel
Merle
M
Cordiglieri
Chiara
C
Odoardi
Francesca
F
Kirchberger
Tanja
T
Kawakami
Naoto
N
Dowden
James
J
Schmid
Frederike
F
Dornmair
Klaus
K
Hohenegger
Martin
M
Flügel
Alexander
A
Guse
Andreas H
AH
Potter
Barry V L
BV
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D009249:NADP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009525:Niacin / Q000494:pharmacology; D009539:Nicotinic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D012433:Ryanodine / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D014316:Tritium; D014803:Vitamin B Complex / Q000494:pharmacology
C543818:3-carboxy-1-octylcarbamoylmethylpyridinium; D050778:NFATC Transcription Factors; D009539:Nicotinic Acids; D019837:Ryanodine Receptor Calcium Release Channel; D014316:Tritium; D014803:Vitamin B Complex; D012433:Ryanodine; D009525:Niacin; D009249:NADP; C024376:NAADP; D002118:Calcium