Whereas sodium–calcium exchangers (NCXs) have long been recognized as plasma membrane constituents that serve to maintain homeostatic concentrations of Ca2+ in the cytoplasm, they were recently shown to also occur in the nuclear envelope (NE) of neural and other cells where they function to regulate nuclear Ca2+. A unique feature of NCXs in the NE is their high-affinity binding to GM1 ganglioside, this association being required for optimal exchanger activity. The NCX–GM1 complex occurs in the inner membrane of the NE and transfers Ca2+ from the nucleoplasm to the NE lumen. In neuronal cells, nuclear GM1 levels are low prior to differentiation but increase rapidly as axonal outgrowth progresses. Cells from genetically altered mice lacking GM1 have limited ability to regulate nuclear Ca2+, and the mice themselves showed similar deficit as seen in their high susceptibility to kainite-induced seizures. These are attenuated by LIGA-20, a derivative of GM1 that enters the nuclear membrane and restores nuclear NCX activity to normal level.