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Journal of Neuroscience, Vol 14, 2272-2281, Copyright © 1994 by Society for Neuroscience
Endogenous ganglioside GM1 modulates L-type calcium channel activity in N18 neuroblastoma cells
RO Carlson, D Masco, G Brooker and S Spiegel
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20007.
Digital imaging fluorescence microscopy was used to investigate the effect
of the B subunit of cholera toxin on calcium homeostasis in neuroblastoma
N18 cells. The B subunit, which binds specifically to ganglioside GM1 in
the outer leaflet of the cell membrane, was found to induce a sustained
increase of intracellular calcium concentration ([Ca2+]i). The increase in
[Ca2+]i was not observed in the absence of extracellular calcium, or in the
presence of the calcium chelator EGTA, and was blocked by nickel. The B
subunit was also found to induce an influx of manganese ions, as indicated
by a quench of the intracellular fura-2 fluorescence. These data suggest
that the B subunit induces an increase in calcium influx in N18 cells.
Potassium-induced depolarization also stimulated manganese influx; however,
after the onset of depolarization-induced influx, the B subunit had no
further effect. This occlusion suggests involvement of voltage-dependent
calcium channels. Treatment with BayK8644, a dihydropyridine agonist
selective for L-type calcium channels, induced manganese influx that was
not altered by the B subunit and apparently blocked the effect of the B
subunit itself. Furthermore, the dihydropyridine L-type channel antagonists
niguldipine or nicardipine completely inhibited B subunit- induced
manganese influx. Thus, the B subunit-induced manganese influx is likely
due to activation of an L-type voltage-dependent calcium channel.
Spontaneous influx of manganese ions was also inhibited by nicardipine or
niguldipine and by exogenous gangliosides. Ganglioside GM1 was more potent
than GM3, but globoside had no significant effect. The modulation of L-type
calcium channels by endogenous ganglioside GM1 has important implications
for its role in neural development, differentiation, and regeneration and
also for its potential function in the electrical excitability of neurons.
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