Sphingolipids of the nucleus and their role in nuclear signaling

Sphingolipids have important signaling and regulatory roles in the nuclei of all vertebrate cells examined to date. Sphingomyelin (SM) is the most abundant of this group and occurs in the nuclear envelope (NE) as well as intranuclear sites. The primary product of SM metabolism is ceramide, whose release by nuclear sphingomyelinase triggers apoptosis and other metabolic changes in the nucleus. Further catabolism results in free fatty acid and sphingosine formation, the latter being capable of conversion to sphingosine phosphate by action of a specific nuclear kinase. Finally, glycosphingolipids such as gangliosides occur in the NE where GM1, one member of the gangliotetraose family, influences Ca2+ flux by activation of a Na+/Ca2+ exchanger located in the inner membrane of the NE. The tightly associated GM1/exchanger complex was shown to exert a cytoprotective role in neurons and other cell types, as absence of this nuclear complex rendered cells vulnerable to apoptosis. A striking example of this mode of Ca2+ regulation is the greatly enhanced seizure activity in knockout mice lacking gangliotetraose gangliosides, involving programmed cell death in the CA3 region of the hippocampus. In this model, Ca2+ homeostasis was restored most effectively with LIGA-20, a membrane-permeant derivative of GM1 that entered the NE and activated the nuclear Na+/Ca2+ exchanger.