Susceptibility of cerebellar granule neurons from GM2/GD2 synthase-null mice to apoptosis induced by glutamate excitotoxicity and elevated KCl: Rescue by GM1 and LIGA20 |
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Authors: | Gusheng Wu Zi-Hua Lu Xin Xie Robert W Ledeen |
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Institution: | Department of Neurology and Neurosciences, New Jersey Medical School-UMDNJ, Newark, New Jersey 07103, USA. |
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Abstract: | Our previous study showed an impaired regulation of Ca(2+) homeostasis in cultured cerebellar granule neurons (CGN) from neonatal mice lacking GM2, GD2 and all gangliotetraose gangliosides, due to disruption of the GM2/GD2 synthase (GalNAc-T) gene. In the presence of depolarizing concentration (55 mM) K(+), these cells showed persistent elevation of intracellular Ca(2+) (Ca(2+)]( i )) leading to apoptosis and cell destruction. This was in contrast to CGN from normal littermates whose survival was enhanced by high K(+). In this study we demonstrate that glutamate has the same effect as K(+) on CGN from these ganglioside-deficient knockout (KO) mice and that apoptosis in both cases is averted by exogenous GM1. Even more effective rescue was obtained with LIGA20, a semi-synthetic derivative of GM1. LC(50) of glutamate in the KO cells was 3.1 microM, compared to 46 microM in normal CGN. Ca(2+)]( i ) measurement with fura-2 revealed no difference in glutamate-stimulated Ca(2+) influx between the 2 cell types. However, reduction of Ca(2+)]( i ) following application of Mg(2+) was significantly impaired in the mutant CGN. The rescuing effects of exogenous GM1 and LIGA20 corresponded to their ability to restore Ca(2+) homeostasis. The greater potency of LIGA20 is attributed to its greater membrane permeability with resultant ability to insert into both plasma and nuclear membranes at low concentration (=1 microM); GM1 at the same concentration was incorporated only into the plasma membrane and required much higher concentration to influence Ca(2+) homeostasis and CGN viability. |
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Keywords: | GM1 ganglioside ganglioside glutamate excitotoxicity apoptosis Ca2+ homeostasis cerebellar granule neurons nuclear envelop nuclear calcium Na+/Ca2+ exchanger |
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