GM1 in the nuclear envelope regulates nuclear calcium through association with a nuclear sodium-calcium exchanger

The inner membrane of the nuclear envelope (NE) of neurons and other cells has been shown to contain GM1 tightly associated with a Na(+)/Ca(2+) exchanger (NCX) whose activity it potentiates in mediating transfer of Ca(2+) from nucleoplasm to the NE lumen. This is consistent with localization of the NCX/GM1 complex in the inner membrane of the NE. NCXs of the plasma membrane, in contrast, appear to bind GM1 much less avidly. This is believed due to different isoforms of NCX in the two membranes, and a difference in topology of NCX relative to GM1. A cytoprotective function for nuclear NCX/GM1 was suggested in the observation that cultured neurons from mice lacking GM1 (GM2/GD2 synthase knockout) were vulnerable to Ca(2+)-induced apoptosis. These neurons in culture were rescued to some extent by GM1 but more effectively by LIGA-20, a membrane-permeant derivative of GM1 that entered the NE. Further indication came from a study of the mutant mice, which were highly susceptible to kainate-induced seizures and could be rescued 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 nuclear NCX.