2004 Fiscal Year Final Research Report Summary
Evidence of a role for cyclic ADP-ribose in calcium signaling and migration in human neutrophils
| Project/Area Number |
15591967
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MORITA Katsuya Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor, 大学院・医歯薬学総合研究科, 助教授 (10116684)
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| Co-Investigator(Kenkyū-buntansha) |
DOHI Toshihiro Hiroshima University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (00034182)
MORIOKA Norimistu Hiroshima University, Graduate School of Biomedical Sciences, Research Associate, 大学院・医歯薬学総合研究科, 助手 (20346505)
KITAYAMA Shigeo Okayama University, Graduate School of Medicine and Dentistry, Professor, 大学院・医歯学総合研究科, 教授 (80177873)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Cyclic ADP-ribose (cADPR) / human neutrophils / Ca^<2+>-mobilization / FK5O6-binding protein (FKBP) / Ryanodine receptor channel / CD38 / Neucleotide transpoter / Chemotaxis |
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| Research Abstract |
Cyclic ADP-ribose (cADPR) has a powerful Ca^<2+>-mobilizing action and behaves as a second messenger of many agonists, thereby modulating a wide number of Ca^<2+>-mediated cell processes. CD38, the best-characterized mammalian ADP-ribosyl cyclase, is postulated to be an important source of cADPR in vivo. Although an increase in [Ca^<2+>]i is a key signal neutrophil functions, the mechanisms for regulation of [Ca^<2+>]i is unclear. The present study examined the regulation by cADPR of Ca^<2+> dynamics and its physiological role in human neutrophils.
cADPR induced Ca^<2+> release from digitonin-permeabilized neutrophils and the release was blocked by 8Br-cADPR, an antagonist of cADPR and FK506 and rapamycin. fMLP and PAF induced a initial rapid rise of [Ca^<2+>]i and the following sustained rise in intact neutrophils. β-NAD^+ added into the medium increased [Ca^<2+>]i. Chemoattractans- and β-NAD^+-induced [Ca^<2+>]i rise were reduced by 8Br-cADPR, anti-CD38 antibody, FK506, rapamycin, NAD
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ase and several nucleoside transporter (NT) inhibitors. ENT_1, ENT_2, CNT_2, CNT_3 are expressed in neutrophils. These results suggest that cADPR synthesized extracellulary by CD38 transported into the cells through NTs and mobilize Ca^<2+> by FK506-binding protein-dependent process and is required for sustained Ca^<2+> influx in neutrophils.
Pretreatment of human neutrophils with either EGTA or 8Br-cADPR specifically blocked the chemotsxis stimulated with fMLP or PAF. Likewise, treatment of neutrophils with FK506, anti-CD38 antibody, NADase and NT inhibitors blocked the chemotaxis to fMLP or PAF. These results demonstrate that neutrophil chemotaxis to fMLP and PAF are dependent on Ca^<2+> mobilization mediated by cADPR.
Thus, cADPR controls neutrophil chemotaxis to chemoattractants through its production of cADPR, and acts as a critical regulator of inflammation and innate immune responses. Since many of the chemoattractant receptors regulated by cADPR bind to ligands that are associated with clinical pathology, cADPR, CD38 and NTs represent novel drug targets with potential application in chronic inflammatory and neurodegenerative disease. Less
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Research Products
(2 results)
