Dopamine-Induced Regulation and Deregulation of the Catabolism of Cyclic ADP-Ribose, an Intrinsic mTOR Signal InhibitorDuring Development in the Rodent Striatum
Dopamine-Induced Regulation and Deregulation of the Catabolism of Cyclic ADP-Ribose, an Intrinsic mTOR Signal InhibitorDuring Development in the Rodent Striatum
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啮齿动物纹状体发育过程中多巴胺诱导的环状 ADP-核糖（一种内在的 mTOR 信号抑制剂）分解代谢的调节和失调
DOI：
10.1166/msr.2013.1019
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Higashida,H
中科院分区：
文献类型：
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作者：
Higashida,C.;Islam,M.S.;Hashii,M.;Higashida,H
尚未在雄性大鼠和小鼠纹状体中研究环ADP-核糖（cADPR）作为多巴胺（DA）受体下游mTOR通路的第二信使和调节剂的作用。为此目的，ADP-核糖基环化酶活性测定使用粗膜部分孵育或不与DA，并通过测量S6激酶（S6 K）磷酸化的分离的纹状体的整个匀浆孵育后，与或不与cADPR。在出生前5天至出生后4天的大鼠和小鼠的膜中，ADP-核糖基环化酶活性始终较低，并且在进一步发育期间增加> 100倍。CD 38的表达随着环化酶活性的增加而增加。出生后1 ~ 3天，DA可刺激环化酶活性，并通过D1和D2样受体使其达到基线水平的2-3倍。此后，DA诱导的增加变得微不足道。可能的cADPR结合蛋白FKBP 12和FKBP 12.6在成年小鼠纹状体中表达。磷酸化与非磷酸化的S6 K的比例降低成年小鼠纹状体孵育5分钟后，在野生型而不是CD 38敲除小鼠的细胞外cADPR的存在下。cADPR的这种抑制作用被雷帕霉素模拟，但通过预先应用8-溴-cADPR而恢复。在毒素诱导的帕金森病模型脑中，cADPR对S6 K的磷酸化作用不太有效。这些结果表明，cADPR在新生儿中以DA敏感的方式产生，在成年纹状体中以DA不敏感但依赖于CD 38的方式产生，并表明cADPR在纹状体细胞中作为内在因子在mTOR通路中起抑制作用。
The role of cyclic ADP-ribose (cADPR) as a second messenger and modulator of the mTOR pathway downstream of dopamine (DA) receptors has not been examined in the male rat and mouse striatum. For this purpose, ADP-ribosyl cyclase activity was measured using a crude membrane fraction incubated with or without DA, and by measuring S6 kinase (S6K) phosphorylation in whole homogenates of the isolated striatum after incubation with or without cADPR. The ADP-ribosyl cyclase activity was consistently low in membranes of 5-day prenatal to 4-day postnatal rats and mice and increased by > 100-fold during further development. Expression of CD38 increased concomitantly with the cyclase activity. From 1 to 3 days postnatal, the cyclase activity could be stimulated by DA and reached a level 2–3-fold higher than the baseline due to D1- and D2-like receptors. Thereafter, the DA-induced increase became marginal. The possible cADPR binding proteins, FKBP12 and FKBP12.6, were expressed in the adult mouse striatum. The ratio of phosphorylated to non-phosphorylated S6K decreased after incubation of adult mouse striatum for 5 min in the presence of extracellular cADPR in wild-type but not CD38 knockout mice. This inhibitory effect of cADPR was mimicked by rapamycin but recovered by prior application of 8-bromo-cADPR. Phosphorylation of S6K by cADPR was less effective in the toxin-induced parkinsonian model brain. These results indicated that cADPR is produced in a DA-sensitive manner in neonates and in a DA-insensitive, but CD38-dependent, manner in the adult striatum and suggest that cADPR plays an inhibitory role in the mTOR pathway as an intrinsic factor in striatal cells.