Over-expression of x-linked inhibitor of apoptosis protein modulates multiple aspects of neuronal Ca2+ signaling

Jeff Grant, Kristen Parker, Craig S. Moore, Paul G.W. Keddy, Michael Mayne, George S. Robertson

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Résumé

X-linked inhibitor of apoptosis (XIAP) protects and preserves the function of neurons in both in vitro and in vivo models of excitotoxicity. Since calcium (Ca2+) overload is a pivotal event in excitotoxic neuronal cell death, we have determined whether XIAP over-expression influences Ca 2+-signaling in primary cultures of mouse cortical neurons. Using cortical neuron cultures derived from wild-type (Wt) mice transiently transfected with XIAP or from transgenic mice that over-express XIAP, we show that XIAP opposes the rise in intracellular Ca2+ concentration by a variety of triggers. Relative to control neurons, XIAP over-expression produced a slight, but significant, elevation of resting Ca2+ concentrations. By contrast, the rise in intracellular Ca2+ concentrations produced by N-methyl-d-aspartate receptor stimulation and voltage gated Ca2+ channel activation were markedly attenuated by XIAP over-expression. The release of Ca2+ from intracellular stores induced by the sarco/endoplasmic reticulum Ca2+ ATPase inhibitor thapsigargin was also inhibited in neurons transiently transfected with XIAP. The pan-caspase inhibitor zVAD did not, however, diminish the rise in intracellular Ca2+ concentrations elicited by l-glutamate suggesting that XIAP influences Ca2+ signaling in a caspase-independent manner. Taken together, these findings demonstrate that the ability of XIAP to block excessive rises in intracellular Ca2+ by a variety of triggers may contribute to the neuroprotective effects of this anti-apoptotic protein.

Langue d'origineEnglish
Pages (de-à)847-856
Nombre de pages10
JournalNeurochemical Research
Volume38
Numéro de publication4
DOI
Statut de publicationPublished - avr. 2013

Note bibliographique

Funding Information:
Acknowledgments This work was supported by the National Research Council of Canada and the Alzheimer’s Society of Canada. Graduate student funding for J Grant was provided by the Alzheimer’s Society of Canada Doctoral Studentship Award and the National Research Council of Canada GSSSP. This work was supported in part by a biomedical research grant from the MS Society of Canada (GSR). The authors would like to thank Dr. Peter Liston for providing the XIAP-dsRed plasmid.

ASJC Scopus Subject Areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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