Gangliosides of the nuclear membrane. GM1 in association with a nuclear Na/Ca exchanger serves a cytoprotective role

Gangliosides were initially viewed primarily as components of the plasma membrane glycocalyx, with little consideration of other loci. This concept was broadened in recent years with recognition of their presence in various intracellular pools as well. The nuclear envelope (NE), consisting of 2 membranes, is one such structure that was shown in our recent studies to contain GM1 ganglioside. Special methodology for separating the 2 membranes revealed GM1 to be situated in the inner membrane of the NE where it is tightly associated with a Na/Caexchanger whose activity it potentiates. This results in the transfer of Ca 2+ from nucleoplasm to the NE lumen, a mechanism for cytoprotection against elevated nuclear Ca 2+ . This is in contrast to Na/Ca exchangers of the plasma membrane which do not bind GM1. This difference is believed due to different isoforms of exchanger, and different topology of exchanger relative to GM1 in the 2 membranes. C6 cells have Na/Ca exchangers only in the NE, and transfer of Ca 2+ from nucleoplasm to NE lumen was revealed with Ca imaging employing the ER‐targeted cameleon Ca fluorescent indicator of Dr. Roger Tsien. Such transfer was blocked by inhibition of the exchanger. Cells lacking the nuclear exchanger were shown to be highly vulnerable to Ca‐induced apoptosis. Cultured neurons from mice genetically engineered to lack GM1 were also highly vulnerable to Ca‐induced apoptosis and were effectively rescued by LIGA‐20, a membrane‐permeant derivative of GM1 that inserts into the NE. GM1 in the NE, in association with Na/Ca exchanger, is thus seen as contributing to regulation of nuclear Ca and exerting a cytoprotective role. Support: NIH grant NS033912.