Physiological role of cyclic ADP-ribose a novel endogenous agonist of ryanodine receptors

环ADP-核糖作为兰尼碱受体的新型内源性激动剂的生理作用

• 批准号: 10470390
• 负责人: MORITA Katsuya
• 金额: $ 8.38万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470390/
• 关键词: cyclic ADP-ribose; ryanodine receptor channel; CaィイD12+ィエD1 mobilization; CaィイD12+ィエD1 -induced CaィイD12+ィエD1 release; ADP-ribosyl cyclase; cyclic AMP; FK506; FK506-binding protein (FKBP); リアノジン受容体チャンネル; Ca^<2+>ーinduced Ca^<2+>release; ADPーribosy

Cyclic ADP-ribose (CADPR) is suggested to be a novel messenger of ryanodine receptors (RyR) in various cellular systems. However, the regulation of its synthesis in response to cell stimulation and its functional roles are still unclear. We examined the physiological relevance of cADPR to the messenger role in stimulation-secretion coupling. The pharmacological profile of the effects of various agents on cADPR-induced CaィイD12+ィエD1 release in digitonin-permeabilized cells suggests that cADPR induces release from different pools via a different mechanism from IP3-induced CaィイD12+ィエD1 release. cADPR-induced CaィイD12+ィエD1 release but not caffeine-, ryanodine-, and IPィイD23ィエD2-induced CaィイD12+ィエD1 release was inhibited by FK506 which bind to FKBPs and dissociate them from the RyR. These evidence suggesting that cADPR may be the ligand for FKBP-RyR complex, resulting in a dynamic regulation of RyR-mediated CaィイD12+ィエD1 release.ADP-ribosyl cyclase was activated in the membrane preparation from … More cells stimulated with acetylcholine (ACh), excess KCl, and 8Br-cAMP, ACh-induced activation of ADP-ribosyl cyclase was dependent on the influx of CaィイD12+ィエD1 into cells and on the activation of cAMP2-dependent protein kinase. These and previous findings that ACh activates adenylate cyclase by CaィイD12+ィエD1 influx, suggested that ACh induces activation of ADP-ribosyl cyclase and CaィイD12+ィエD1 influx through the cAMP-mediated pathways.ACh causes biphasic [CaィイD12+ィエD1]i rise, an initial transient rise followed by sustained rise, in intact cells. 8Br-cADPR, an antagonist of cADPR and FK506 specifically reduced the sustained phases of ACh-induced [CaィイD12+ィエD1]i rise. 8Br-cADPR, and FK506 failed to alter ACh-Induced [CaィイD12+ィエD1]i rise pretreated with RyR antagonist, imperatoxin inhibitor (IpTxi), suggesting that cADPR contributes to [CaィイD12+ィエD1]i rise following peak [CaィイD12+ィエD1]i rise. 8Br cADPR FK506, and IpTxi reduced CA release in response to ACh in chromaffin cells.These results provide evidence that the synthesis of cADPR Is regulated by cell stimulation, and the cADPR/ CaィイD12+ィエD1-induced CaィイD12+ィエD1 release pathway forms a significant signal transduction for secretion. Less

环腺苷二磷酸核糖（CADPR）被认为是一种新的信使的兰尼碱受体（RyR）在各种细胞系统。然而，其合成的调控响应细胞刺激和其功能作用仍然不清楚。我们研究了cADPR在刺激-分泌偶联中的信使作用的生理相关性。在毛地黄皂苷透化细胞中，各种药物对cADPR诱导的Ca ~（2+）D12+ Ca ~（2+）D1释放的药理学作用表明，cADPR通过与IP 3诱导的Ca ~（2+）D12+ Ca ~（2+）D1释放不同的机制诱导不同池的释放。FK 506可抑制cADPR诱导的Ca ~（2+）D_1释放，但不抑制咖啡因、兰尼定和IP β_23 β_2 D_2诱导的Ca ~（2+）D_1释放，FK 506可与FKBP结合并使其与RyR解离。这些证据表明，cADPR可能是FKBP-RyR复合物的配体，导致RyR介导的Ca ~（2+）D_1释放的动态调节。 ...更多信息 用乙酰胆碱（ACh）、过量KCl和8Br-cAMP刺激细胞，ACh诱导的ADP-核糖基环化酶的激活依赖于Ca ~（2+）D_12 + cAMP D_1流入细胞和cAMP_2依赖性蛋白激酶的激活。ACh通过cAMP介导的途径激活腺苷酸环化酶和Ca ~（2+）D_（12+）D_（11）内流，引起完整细胞内[Ca ~（2+）D_（12+）D_（11）]i双相升高。cADPR拮抗剂8Br-cADPR和FK 506可特异性地降低ACh诱导的[Ca ~（2+）D_1]i升高的持续时相。8 Br-cADPR和FK 506不能改变RyR拮抗剂、Imperatoxin抑制剂（IpTxi）预处理的ACh诱导的[Ca ~（2+）D_1]i升高，提示cADPR参与[Ca ~（2+）D_1] i升高后[Ca ~（2+）D_1] i的峰值升高。8Br cADPR FK 506和IpTxi可抑制ACh引起的肾上腺嗜铬细胞CA释放，提示cADPR的合成受细胞刺激的调节，cADPR/ Ca ~（2+）D_12 + Ca ~（2+）D_1诱导的Ca ~（2+）D_12 + Ca ~（2+）D_1释放途径是分泌的重要信号转导途径。少

项目成果

森田克也: "Ca^<2+>動員物質サイクリックADPリボースの合成酵素および細胞膜輸送体としてのCD38"ファルマシア. 35・9. 946-947 (1999)

Katsuya Morita：“CD38 作为 Ca ^ 2+ 动员物质环状 ADP 核糖的合酶和细胞膜转运蛋白” Pharmacia 35·9（1999）。

Yamaki Hiroshi: "Cyclic ADP-riboser induse CaィイD12+ィエD1 release from caffeine-insencitive CaィイD12+ィエD1 pools in salivarygland cells"Journal of Dental Research. 77-10. 1807-1816 (1998)

Hiroshi Yamaki：“唾液腺细胞中咖啡因不敏感的 CaiD12+D1 池中的环状 ADP-核糖酶释放 CaD12+D1”《牙科研究杂志》77-10（1998）。

Yamaki Hiroshi: "Cyclic ADP-ribose induces Ca^<2+>release from caffeine-insensitive Ca^<2+>pools in canine salivary gland cells" Journal of Dental Research. 77・10. 1807-1816 (1998)

Hiroshi Yamaki：“环状 ADP-核糖诱导犬唾液腺细胞中对咖啡因不敏感的 Ca^<2+> 池中的 Ca^<2+> 释放”，《牙科研究杂志》77・10（1998）。

Yamaki Hiroshi: "Cyclic ADP-ribose induced Ca^<2+> release from caffeine-insensitive Ca^<2+> pools in canine salivary gland cells"Journal of Dental Research. 77・10. 1807-1816 (1998)

Hiroshi Yamaki：“犬唾液腺细胞中咖啡因不敏感的 Ca^<2+> 池中的环状 ADP-核糖诱导 Ca^<2+> 释放”，《牙科研究杂志》77・10 (1998)。

森田克也: "Ca^<2+>動員物質サイクリックADPリボースの合成酵素及び細胞膜輸送体としてのCD38"ファルマシア. 35・9. 946-947 (1999)

Katsuya Morita：“CD38 作为 Ca^2+ 动员物质环 ADP 核糖的合酶和细胞膜转运蛋白”Pharmacia 35·946-947 (1999)。