Gangliosides of the nuclear membrane: a crucial locus of cytoprotective modulation

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.