Ledeen Robert W, Wu Gusheng
Department of Neurology and Neurosciences, New Jersey Medical School-UMDNJ, 185 South Orange Avenue, Newark, New Jersey 07103, USA.
J Cell Biochem. 2006 Apr 1;97(5):893-903. doi: 10.1002/jcb.20731.
The original concept of gangliosides as localized components of the plasma membrane has broadened in recent years with recognition of their presence in various intracellular pools as well. The nuclear envelope (NE), consisting of two unique membranes, is one such structure shown to contain members of the gangliotetraose family and possibly other sialoglycolipids. GM1 situated in the inner membrane of the NE is tightly associated with a Na+/Ca2+ exchanger whose activity it potentiates in the transfer of Ca2+ from nucleoplasm to the NE lumen. This is in contrast to Na+/Ca2+ exchangers of the plasma membrane which bind GM1 less avidly or not at all. This is believed due to different isoforms of exchanger, and a difference in topology of the exchanger relative to GM1. Cultured neurons from mice genetically engineered to lack gangliotetraose gangliosides such as GM1 were highly vulnerable to Ca2+-induced apoptosis. They were rescued to some extent by GM1 but more effectively by LIGA-20, a membrane-permeant derivative of GM1 that traverses the plasma membrane more effectively than GM1 and inserts into the NE. As further indication of Ca2+ dysregulation, the mutant mice were highly susceptible to kainite-induced seizures which were attenuated by LIGA-20. This correlated with the ability of LIGA-20 to cross the blood-brain barrier, enter brain cells, insert into the NE, and potentiate the nuclear exchanger. GM1 in the NE, in association with nuclear Na+/Ca2+ exchanger, is thus seen as contributing to Ca2+ regulation within the nucleus and in the process exerting a cytoprotective role.
近年来，随着神经节苷脂在各种细胞内池中的存在被认识到，其作为质膜局部成分的原始概念得到了扩展。由两个独特膜组成的核膜（NE）就是这样一种结构，已显示其含有神经节四糖家族的成员以及可能的其他唾液酸糖脂。位于NE内膜的GM1与一种Na+/Ca2+交换器紧密相关，它在将Ca2+从核质转移到NE腔的过程中增强了该交换器的活性。这与质膜的Na+/Ca2+交换器形成对比，后者与GM1的结合不那么紧密或根本不结合。这被认为是由于交换器的不同异构体以及交换器相对于GM1的拓扑结构差异所致。从经过基因工程改造而缺乏神经节四糖神经节苷脂（如GM1）的小鼠中培养的神经元对Ca2+诱导的凋亡高度敏感。它们在一定程度上被GM1挽救，但更有效地被LIGA-20挽救，LIGA-20是GM1的一种膜渗透性衍生物，比GM1更有效地穿过质膜并插入NE。作为Ca2+调节异常的进一步迹象，突变小鼠对红藻氨酸诱导的癫痫发作高度敏感，而LIGA-20可减轻这种发作。这与LIGA-20穿过血脑屏障、进入脑细胞、插入NE并增强核交换器的能力相关。因此，NE中的GM1与核Na+/Ca2+交换器相关联，被视为有助于细胞核内的Ca2+调节，并在此过程中发挥细胞保护作用。
