GM1 ganglioside: another nuclear lipid that modulates nuclear calcium. GM1 potentiates the nuclear sodium–calcium exchangerThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

Abstract

The nuclear envelope (NE) enclosing the cell nucleus, although morphologically and chemically distinct from the plasma membrane, has certain features in common with the latter including the presence of GM1 as an important modulatory molecule. This ganglioside influences Ca(2+) flux across both membranes, but by quite different mechanisms. GM1 in the NE contributes to regulation of nuclear Ca(2+) through potentiation of a Na(+)/Ca(2+) exchanger in the inner nuclear membrane, whereas in the cell membrane, it regulates cytosolic Ca(2+) through modulation of a nonvoltage-gated Ca(2+) channel. Studies with neuroblastoma cells suggest GM1 concentration becomes elevated in the NE with onset of axonogenesis. However, the nuclear GM1/exchanger complex is not limited to neuronal cells but also occurs in NE of astrocytes, C6 cells, and certain non-neural cells. Immunoprecipitation and immunoblot experiments have shown high affinity association of the nuclear Na(+)/Ca(2+) exchanger with GM1, in contrast to Na(+)/Ca(2+) exchangers of the plasma membrane, which bind GM1 less avidly or not at all. This is believed to be due to different isoforms of the exchanger and a difference in topology of GM1 relative to the large inner loop of the exchanger in the 2 membranes. Cultured neurons from mice genetically engineered to lack GM1 suffered Ca(2+) dysregulation as seen in their high vulnerability to Ca(2+)-induced apoptosis. They were rescued by GM1 and more effectively by LIGA20, a membrane-permeant derivative of GM1. The mutant animals were highly susceptible to kainate-induced seizures, which are also a reflection of Ca(2+) dysregulation. The seizures were effectively attenuated by LIGA20 in parallel with the ability of this agent to enter brain cells, insert into the NE, and potentiate Na(+)/Ca(2+) exchange activity in the nucleus. The Na(+)/Ca(2+) exchanger of the NE, in association with nuclear GM1, is thus seen contributing to independent regulation of Ca(2+) by the nucleus in a manner that provides cytoprotection against Ca(2+)-induced apoptosis.

Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases

“…GM1 is one of the most abundant gangliosides present in the adult neuronal membranes, and is the only ganglioside shown to bind Ca 2+ and to modulate Ca 2+ flux across membranes (Figs. 2 and 3 ) 52 , 102 , 108 , 117 , 118 .…”

Lysosomal multienzyme complex: pros and cons of working together

“…These include the inositol trisphosphate receptor (IP3R) at the ER face of the MAMs, the molecular chaperone glucose-regulated-protein 75 (grp75), which bridges the IP3R-1 with voltage-dependent anion channel 1 (VDAC1) at the outer mitochondrial membrane, Sigma-1 receptor, calreticulin, mitofusin 2, and phosphofurin acidic cluster sorting protein 2 [94–97]. Due to the intrinsic ability of G M1 to bind Ca 2+ [98, 99], we hypothesized that, if this ganglioside would be present in these specialized microdomains, it could influence the Ca 2+ conductance and buffer capacity of the MAMs. Ultrastructural analyses of crude β-Gal −/− mitochondrial preparations revealed numerous juxtaposed ER vesicles, which were indicative of increased contact sites between ER and mitochondrial membranes.…”

Glycosphingolipid Structure and Function in Membranes

“…Although the function of nuclear gangliosides is largely unknown, nuclear GM1 was found to be associated with and to potently and specifically activate a Na + /Ca 2+ exchanger in NG108-15 neuroblastoma, implying its role in nuclear calcium homeostasis [154]. This effect was highly specific since the plasma membrane isoform of the Na + /Ca 2+ exchanger neither bound GM1 avidly nor was modulated by this ganglioside [155]. Apart from this specific effect of GM1 on nuclear calcium homeostasis gangliosides are believed to be involved in endoplasmic reticulum calcium homeostasis, which is often associ- ated with integrity of the mitochondrial membranes and ultimately with programmed cell death (for review see [156]).…”