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 Ca2+flux across both membranes, but by quite different mechanisms. GM1 in the NE contributes to regulation of nuclear Ca2+through potentiation of a Na+/Ca2+exchanger in the inner nuclear membrane, whereas in the cell membrane, it regulates cytosolic Ca2+through modulation of a nonvoltage-gated Ca2+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+/Ca2+exchanger with GM1, in contrast to Na+/Ca2+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 Ca2+dysregulation as seen in their high vulnerability to Ca2+-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 Ca2+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+/Ca2+exchange activity in the nucleus. The Na+/Ca2+exchanger of the NE, in association with nuclear GM1, is thus seen contributing to independent regulation of Ca2+by the nucleus in a manner that provides cytoprotection against Ca2+-induced apoptosis.