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

Cyclic ADP-ribose （CADPR） is suggested to be a novel messenger of ryanodine receptors （RyR） in various cellular systems。However，对细胞刺激的反应及其功能作用仍然不清楚的规则。我们研究了cADPR对信使在刺激-保密组合中的作用的生理学相关性。The pharmacological profile of the effects of various agents on cADPR-induced CaイイD12+イエD1 release in digitonin-permeManagement ized cells suggests that cADPR induces release from different pools via a different mManagement ism from IP3-induced CaイD12+イエD1 release。cADPR-induced CaイイD12+イエD1 release but not caffine-，ryanodine-， and IPイイD23イエD2-induced CaイイD12+イエD1 release was inhibited by FK506 which bind to FKBPs and dissociate them from the RyR.这些证据建议cADPR可能是FKBP-RyR复合体的配体，在RyR介导的CaiD 12 + RyiD 1释放的动态调节中结果，ADP-核糖基环酶在膜制备中激活 ... More 细胞用乙酰胆碱素（ACh）、Excess KCl和8Br-cAMP刺激，以及ACh诱导的ADP-核糖基环酶依赖于Cai-D12 + i-D1在细胞中的影响和激活cAMP 2-依赖蛋白激酶。这些和先前的发现，通过Cai-D12 + i-D1 inlux激活了ACh诱导的ADP-ribosyl cyclase和Cai-D12 + i-D1 inlux通过cAMP介导的路径. ACH causes biphasic [Cai-D12 + i-D1]i rise， an initial transient rise followed by sustained rise， in intact cells。8 Br-cADPR， an antagonist of cADPR and FK506 specifically reduced the sustained phases of Ach-induced [CaイイD12+イエD1]i rise。8 Br-cADPR， and FK506 failed to alter ACh-Induced [CaイイD12+イエD1]i rise pretreated with RyR antagonist， imperatoxin inhibitor （IpTxi）， suggesting that cADPR contributes to [CaイD12+イエD1]i rise following peak [CaイD12+イエ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イD12 + yイD1 release pathway forms a significant signal transduction for secretion。Less（低）

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