New findings on nuclear gangliosides: overview on metabolism and function

GM1 and GD1a gangliosides occur in both membranes of the nuclear envelope (NE) together with two isoforms of neuraminidase. The Neu3 isoform of neuraminidase occurs in the inner membrane of the NE and Neu1 in the outer membrane. Both isoforms convert GD1a to GM1 within the respective membranes. GM1 in the inner membrane is tightly associated with a Na+/Ca2+ exchanger (NCX) and potentiates the latter's activity. The NCX/GM1 complex mediates transfer of nucleoplasmic Ca2+ to the NE lumen and hence to the endoplasmic reticulum (ER) with which it is continuous. Since cytoplasmic- and nucleoplasmic Ca2+ are in homeostatic equilibrium (via nuclear pores), the nuclear NCX/GM1 complex acts to gate Ca2+ transfer from cytosol to ER via nucleoplasm and NE. This constitutes an alternate route to the SERCA pump, indicating the influence of nuclear NCX/GM1 on whole cell Ca2+ homeostasis. Use of cameleon-fluorescent Ca2+ indicators (R. Tsien) demonstrated no Ca2+ transfer from cytosol/nucleoplasm to ER in cells lacking nuclear NCX (Jurkat), and significantly reduced Ca2+ transfer in cells lacking nuclear GM1 (NG-CR72). NCX/GM1 appears in the NE of neurons as they differentiate and serves a cytoprotective function, as seen in the high susceptibility of GalNAcT-/- knockout mice to kainate-induced seizure activity. This was alleviated by intraperitoneal injections of LIGA-20 a derivative of GM1 that is able (unlike GM1 itself) to traverse the blood brain barrier and neuronal plasma membrane and insert into the NE where it restores NCX exchanger activity. Absence or loss of nuclear GM1 renders cells vulnerable to apoptotic elimination.