| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Trudeau Institute, Saranac Lake, NY 12983;
Department of Pediatrics, Columbus Children’s Research Institute, Columbus, OH 43205;
The Calcium Signalling Group, Institute of Biochemistry and Molecular Biology I: Cellular Signal Transduction, Center of Experimental Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany; and
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455
The ectoenzyme CD38 catalyzes the production of cyclic ADP-ribose (cADPR) and ADP-ribose (ADPR) from its substrate, NAD+. Both products of the CD38 enzyme reaction play important roles in signal transduction, as cADPR regulates calcium release from intracellular stores and ADPR controls cation entry through the plasma membrane channel TRPM2. We previously demonstrated that CD38 and the cADPR generated by CD38 regulate calcium signaling in leukocytes stimulated with some, but not all, chemokines and controls leukocyte migration to inflammatory sites. However, it is not known whether the other CD38 product, ADPR, also regulates leukocyte trafficking In this study we characterize 8-bromo (8Br)-ADPR, a novel compound that specifically inhibits ADPR-activated cation influx without affecting other key calcium release and entry pathways. Using 8Br-ADPR, we demonstrate that ADPR controls calcium influx and chemotaxis in mouse neutrophils and dendritic cells activated through chemokine receptors that rely on CD38 and cADPR for activity, including mouse FPR1, CXCR4, and CCR7. Furthermore, we show that the calcium and chemotactic responses of leukocytes are not dependent on poly-ADP-ribose polymerase 1 (PARP-1), another potential source of ADPR in some leukocytes. Finally, we demonstrate that NAD+ analogues specifically block calcium influx and migration of chemokine-stimulated neutrophils without affecting PARP-1-dependent calcium responses. Collectively, these data identify ADPR as a new and important second messenger of mouse neutrophil and dendritic cell migration, suggest that CD38, rather than PARP-1, may be an important source of ADPR in these cells, and indicate that inhibitors of ADPR-gated calcium entry, such as 8Br-ADPR, have the potential to be used as anti-inflammatory agents.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by National Institutes of Health Grant AI057996 and the Trudeau Institute (to F.E.L.), Deutsche Forschungsgemeinschaft Grants GU 360/9-1 and 9-2 and the Gemeinnützige Hertie-Stiftung (to A.H.G.), and National Institutes of Health Grant DA11806 (to T.F.W.).
2 Current address: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, CT 06520.
3 Address correspondence and reprint requests to Dr. Frances Lund, Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, NY 12983. E-mail address: flund{at}trudeauinstitute.org
4 Abbreviations used in this paper: IP3, D-myo-inositol 1,4,5-trisphosphate; ADPR, ADP-ribose; B6, C57BL/6J; 8-Br, 8-bromo; cADPR, cyclic ADP-ribose; CI, chemotactic index; DC, dendritic cell; FPR, N-formyl peptide receptor; NAADP+, nicotinic acid adenine dinucleotide phosphate; PARG, poly-ADP-ribose glycohydrolase; PARP-1, poly-ADP-ribose polymerase 1; RyR, ryanodine receptors; SOC, store-operated channel; TFA, trifluoroacetic acid; WT, wild type.
This article has been cited by other articles:
|
|
 |
|
  I. Lange, S. Yamamoto, S. Partida-Sanchez, Y. Mori, A. Fleig, and R. Penner TRPM2 Functions as a Lysosomal Ca2+-Release Channel in {beta} Cells Sci. Signal., May 19, 2009; 2(71): ra23 - ra23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Koch-Nolte, F. Haag, A. H. Guse, F. Lund, and M. Ziegler Emerging Roles of NAD+ and Its Metabolites in Cell Signaling Sci. Signal., February 10, 2009; 2(57): mr1 - mr1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Hermosura, A. M. Cui, R. C. V. Go, B. Davenport, C. M. Shetler, J. W. Heizer, C. Schmitz, G. Mocz, R. M. Garruto, and A.-L. Perraud Altered functional properties of a TRPM2 variant in Guamanian ALS and PD PNAS, November 18, 2008; 105(46): 18029 - 18034. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. L. Southgate, R. L. He, J.-L. Gao, P. M. Murphy, M. Nanamori, and R. D. Ye Identification of Formyl Peptides from Listeria monocytogenes and Staphylococcus aureus as Potent Chemoattractants for Mouse Neutrophils J. Immunol., July 15, 2008; 181(2): 1429 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Roy, S. Khanna, C. Rink, S. Biswas, and C. K. Sen Characterization of the acute temporal changes in excisional murine cutaneous wound inflammation by screening of the wound-edge transcriptome Physiol Genomics, July 1, 2008; 34(2): 162 - 184. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C. Rodriguez-Alba, M. E. Moreno-Garcia, C. Sandoval-Montes, V. H. Rosales-Garcia, and L. Santos-Argumedo CD38 induces differentiation of immature transitional 2 B lymphocytes in the spleen Blood, April 1, 2008; 111(7): 3644 - 3652. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
