CD38 disruption impairs glucose-induced increases in cyclic ADP-ribose, [Ca2+]i, and insulin secretion
CD38 disruption impairs glucose-induced increases in cyclic ADP-ribose, [Ca2+]i, and insulin secretion
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DOI：
10.1074/jbc.274.4.1869
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发表时间：
1999-01-22
影响因子：
4.8
通讯作者：
Okamoto, H
中科院分区：
文献类型：
--
作者：
Kato, I;Yamamoto, Y;Okamoto, H
胰腺β细胞中[Ca 2 +]（i）的增加，由细胞内储存的Ca 2+动员以及细胞外来源的Ca 2+流入引起，在葡萄糖分泌胰岛素中很重要。已经假定通过葡萄糖刺激在β细胞中积累的环状ADP-核糖（cADPR）充当细胞内Ca 2+动员以用于胰岛素分泌的第二信使，并且认为CD 38参与cADPR积累（Takasawa，S.，Tohgo，k，Noguchi，N，Koguma，T，Nata，K，Sugimoto，T，Yonekura，H.，，和Okamoto，H，（1993）J. Biol. Chem，268，26052-26054）。通过同源重组，CD 38（-/-）小鼠发育正常，但在胰岛中葡萄糖诱导的cADPR产生中没有显示出增加，CD 38（-/-）胰岛对葡萄糖诱导的[Ca ~（2+）]（i）升高和胰岛素分泌均严重受损，而CD 38（-/-）胰岛对细胞外Ca ~（2+）内流刺激剂甲苯磺丁脲和KCl反应正常，CD 38（-/-）小鼠表现出糖耐量受损，血清胰岛素水平低于对照组，而这些受损的表型可通过CD 38 cDNA的β细胞特异性表达得到挽救。这些结果表明，CD 38在cADPR动员细胞内Ca 2+以分泌胰岛素中起重要作用。
Increases in [Ca2+](i) in pancreatic beta cells, resulting from Ca2+ mobilization from intracellular stores as well as Ca2+ influx from extracellular sources, are important in insulin secretion by glucose. Cyclic ADP-ribose (cADPR), accumulated in beta cells by glucose stimulation, has been postulated to serve as a second messenger for intracellular Ca2+ mobilization for insulin secretion, and CD38 is thought to be involved in the cADPR accumulation (Takasawa, S,, Tohgo, k, Noguchi, N,, Koguma, T,, Nata, K,, Sugimoto, T,, Yonekura, H.,, and Okamoto, H, (1993) J. Biol. Chem, 268, 26052-26054), Here we created "knockout" (CD38(-/-)) mice by homologous recombination, CD38(-/-) mice developed normally but showed no increase in their glucose-induced production of cADPR in pancreatic islets, The glucose-induced [Ca2+](i) rise and insulin secretion were both severely impaired in CD38(-/-) islets, whereas CD38(-/-) islets responded normally to the extracellular Ca2+ influx stimulants tolbutamide and KCl, CD38(-/-) mice showed impaired glucose tolerance, and the serum insulin level was lower than control, and these impaired phenotypes were rescued by beta cell-specific expression of CD38 cDNA These results indicate that CD38 plays an essential role in intracellular Ca2+ mobilization by cADPR for insulin secretion.