Gangliosides of the nuclear membrane: A crucial locus of cytoprotective modulation

Abstract

The original concept of gangliosides as localized components of the plasma membrane has broadened in recent years with recognition of their presence in various intracellular pools as well. The nuclear envelope (NE), consisting of two unique membranes, is one such structure shown to contain members of the gangliotetraose family and possibly other sialoglycolipids. GM1 situated in the inner membrane of the NE is tightly associated with a Na þ /Ca 2þ exchanger whose activity it potentiates in the transfer of Ca 2þ from nucleoplasm to the NE lumen. This is in contrast to Na þ /Ca 2þ exchangers of the plasma membrane which bind GM1 less avidly or not at all. This is believed due to different isoforms of exchanger, and a difference in topology of the exchanger relative to GM1. Cultured neurons from mice genetically engineered to lack gangliotetraose gangliosides such as GM1 were highly vulnerable to Ca 2þ -induced apoptosis. They were rescued to some extent by GM1 but more effectively by LIGA-20, a membrane-permeant derivative of GM1 that traverses the plasma membrane more effectively than GM1 and inserts into the NE. As further indication of Ca 2þ dysregulation, the mutant mice were highly susceptible to kainite-induced seizures which were attenuated 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 the nuclear exchanger. GM1 in the NE, in association with nuclear Na þ /Ca 2þ exchanger, is thus seen as contributing to Ca 2þ regulation within the nucleus and in the process exerting a cytoprotective role.

A new, long-wavelength borondipyrromethene sphingosine for studying sphingolipid dynamics in live cells

“…To our knowledge, this is the fi rst observation of fl uorescent sphingosine metabolite association with DNA in the nucleus of a living cell, although further studies are required to confi rm the BODIPY 540-labeled molecule was BODIPY 540 sphingomyelin. Since their detection in the nucleus decades ago ( 42,43 ), the identities and subnuclear distributions of sphingolipids have been primarily probed by biochemical analysis of isolated nuclei and visualization of sphingolipid-specifi c functionalized affi nity labels ( 2,44,45 ). Additionally, structural and regulatory roles performed by various types of sphingolipids in the nucleus have been identifi ed ( 2 ).…”

“…Additionally, structural and regulatory roles performed by various types of sphingolipids in the nucleus have been identifi ed ( 2 ). Sphingomyelin associates with chromatin and stabilizes DNA and newly synthesized RNA ( 45,46 ), GM1 regulates nuclear calcium concentrations ( 44 ), and nuclear ceramide is involved in proliferation and apoptosis, although the precise mechanisms remain to be established ( 47-49 ). As mentioned above, nuclear sphingosine-1-phosphate regulates gene expression by binding to histone deacetylases, thereby inhibiting histone deacetylation ( 34 ).…”

Sodium-calcium exchanger complexed with GM1 ganglioside in nuclear membrane transfers calcium from nucleoplasm to endoplasmic reticulum

“…Exchanger-mediated transfer of Ca 2ϩ to the NE can presumably be reversed, as with plasma membrane NCX (25), thus providing a potential route for Ca 2ϩ flux from ER/NE to nucleoplasm and cytosol. We have postulated that in addition to the presence of different isoforms, NCX assumes different topological orientations in these 2 membranes that would help explain differences in affinity toward GM1 (13,29). Evidence for charge-charge interaction between NCX and GM1 in the NE has been reported (16).…”

“…However, some studies have suggested the existence of cytoplasmnucleoplasm Ca 2ϩ gradients (9,10), and there is growing evidence for independent Ca 2ϩ regulation in that organelle (11). Adding to the story was the discovery of a mechanism for Ca 2ϩ flux between NE and nucleoplasm, mediated by sodium-calcium exchanger (NCX) activity in the inner membrane of the NE of neural-and certain other cells; analyses that revealed the latter exchanger included immunoprecipitation/immunoblotting (IP/IB), immunocytochemistry, RT-PCR, and 45 Ca 2ϩ uptake by the NE of isolated nuclei (12,13). A key feature of this NCX was its potentiation by GM1 ganglioside with which it forms a high affinity complex that survives SDS/PAGE.…”

In Search of a Solution to the Sphinx-Like Riddle of GM1

“…. Several isoforms of NCX are known to exist [44,45] and we have speculated that specific forms with greater abundance of positively-charged amino acids are the ones that predominate in the NE [46].…”