Johnson James D, Han Zhiqiang, Otani Kenichi, Ye Honggang, Zhang Yan, Wu Hong, Horikawa Yukio, Misler Stanley, Bell Graeme I, Polonsky Kenneth S
Department of Internal Medicine, Washington University, St. Louis, Missouri 63110, USA.
J Biol Chem. 2004 Jun 4;279(23):24794-802. doi: 10.1074/jbc.M401216200. Epub 2004 Mar 25.
Cells are programmed to die when critical signaling and metabolic pathways are disrupted. Inhibiting the type 2 ryanodine receptor (RyR2) in human and mouse pancreatic beta-cells markedly increased apoptosis. This mode of programmed cell death was not associated with robust caspase-3 activation prompting a search for an alternative mechanism. Increased calpain activity and calpain gene expression suggested a role for a calpain-dependent death pathway. Using a combination of pharmacological and genetic approaches, we demonstrated that the calpain-10 isoform mediated ryanodine-induced apoptosis. Apoptosis induced by the fatty acid palmitate and by low glucose also required calpain-10. Ryanodine-induced calpain activation and apoptosis were reversed by glucagon-like peptide or short-term exposure to high glucose. Thus RyR2 activity seems to play an essential role in beta-cell survival in vitro by suppressing a death pathway mediated by calpain-10, a type 2 diabetes susceptibility gene with previously unknown function.
当关键信号传导和代谢途径被破坏时，细胞会被编程死亡。在人和小鼠胰腺β细胞中抑制2型兰尼碱受体（RyR2）会显著增加细胞凋亡。这种程序性细胞死亡模式与强大的半胱天冬酶-3激活无关，促使人们寻找替代机制。钙蛋白酶活性和钙蛋白酶基因表达增加表明钙蛋白酶依赖性死亡途径发挥了作用。通过药理学和遗传学方法的结合，我们证明钙蛋白酶-10亚型介导了兰尼碱诱导细胞凋亡。脂肪酸棕榈酸酯和低葡萄糖诱导的细胞凋亡也需要钙蛋白酶-10。胰高血糖素样肽或短期暴露于高葡萄糖可逆转兰尼碱诱导的钙蛋白酶激活和细胞凋亡。因此，RyR2活性似乎通过抑制由钙蛋白酶-10介导的死亡途径在体外β细胞存活中起重要作用，钙蛋白酶-10是一种2型糖尿病易感基因，其功能以前未知。
