Evidence of a role for cyclic ADP-ribose in calcium signaling and migration in human neutrophils

环 ADP-核糖在人中性粒细胞钙信号传导和迁移中作用的证据

基本信息

批准号：
15591967
负责人：
MORITA Katsuya
金额：
$ 1.92万
依托单位：
HIROSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

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 … More 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

循环ADP -ribose（CADPR）具有强大的Ca^<2+> - 动作，并作为许多激动剂Ca^<2+>介导的细胞过程的第二个使者。假设是CADPR在体内的重要sorce，EY信号中性粒细胞功能，调节[Ca^<2 +>]的机制尚不清楚。 <2+>从渗透性的中性粒细胞中释放，并被8BR-CADPR（CADPR的拮抗剂和FK506和RapaMycin）释放。 I.Chemoattractans-and β-nad^+-induced Ycin, nad… More ASE and SEVERAL NUCLEOSIDE TRANSPORTER (NT) INHIBITORS. ENT_1, CNT_2 Ynthesized ExtraCellulary by CD38 Transported Into The Cells THE CELLS THE CD38 THE CELLS THE CD38 THE CELLS THE CELLS细胞细胞细胞细胞细胞细胞细胞的细胞细胞cels cel的一定依赖性过程，是持续的Ca^<2+> inutrophils所必需的。人嗜中性粒细胞的预测枯萎了EGTA或8BR -CADPR或8BR -cADPR，themotsxis sigtlp或paf。同样，用FK506，抗CD38抗体，NADase和NT抑制剂对中性粒细胞的治疗将其阻塞至FMLP或PAF，这些结果表明，在Ca^<2+>移动中，对FMLP的Neuthil趋化，CADPR通过产生CADPR来控制中性粒细胞趋化因素，并作为对临床病理学，CADPR，CD38和NTS抑制新型药物靶标的潜在应用在慢性膜和神经脱发疾病中的临床病理学的批判性调节剂。较少的