Abstract
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^+^/Ca^2+^ exchanger whose activity it potentiates in the transfer of Ca^2+^ from nucleoplasm to the NE lumen. This is in contrast to Na^+^/Ca^2+^ 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 Ca^2+^โinduced apoptosis. They were rescued to some extent by GM1 but more effectively by LIGAโ20, a membraneโpermeant derivative of GM1 that traverses the plasma membrane more effectively than GM1 and inserts into the NE. As further indication of Ca^2+^ dysregulation, the mutant mice were highly susceptible to kainiteโinduced seizures which were attenuated by LIGAโ20. This correlated with the ability of LIGAโ20 to cross the bloodโbrain barrier, enter brain cells, insert into the NE, and potentiate the nuclear exchanger. GM1 in the NE, in association with nuclear Na^+^/Ca^2+^ exchanger, is thus seen as contributing to Ca^2+^ regulation within the nucleus and in the process exerting a cytoprotective role. J. Cell. Biochem. 97: 893โ903, 2006. ยฉ 2006 WileyโLiss, Inc.