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

Gusheng Wu, Zi Hua Lu, Xin Xie, Robert W. Ledeen

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42 Scopus citations

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 μM, compared to 46 μM 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 (≤1μM); 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.

Original languageEnglish (US)
Pages (from-to)305-313
Number of pages9
JournalGlycoconjugate Journal
Volume21
Issue number6
DOIs
StatePublished - 2004

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Keywords

  • Ca homeostasis
  • GM1 ganglioside
  • Na /Ca exchanger
  • apoptosis
  • cerebellar granule neurons
  • ganglioside
  • glutamate excitotoxicity
  • nuclear calcium
  • nuclear envelop

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