title: Over-expression of X-linked inhibitor of apoptosis protein modulates multiple aspects of neuronal Ca2+ signaling.
abstract: 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 (Ca(2+)) 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 Ca(2+) concentration by a variety of triggers. Relative to control neurons, XIAP over-expression produced a slight, but significant, elevation of resting Ca(2+) concentrations. By contrast, the rise in intracellular Ca(2+) concentrations produced by N-methyl-D-aspartate receptor stimulation and voltage gated Ca(2+) channel activation were markedly attenuated by XIAP over-expression. The release of Ca(2+) from intracellular stores induced by the sarco/endoplasmic reticulum Ca(2+) 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 Ca(2+) concentrations elicited by L-glutamate suggesting that XIAP influences Ca(2+) signaling in a caspase-independent manner. Taken together, these findings demonstrate that the ability of XIAP to block excessive rises in intracellular Ca(2+) by a variety of triggers may contribute to the neuroprotective effects of this anti-apoptotic protein.
authors: Institute for Nutrisciences and Health, National Research Council of Canada, Charlottetown PEI, C1A 4P3, Canada. jgrant@med.miami.edu
authors: Jeff
authors: J
authors: Grant
authors: Kristen
authors: K
authors: Parker
authors: Craig S
authors: CS
authors: Moore
authors: Paul G W
authors: PG
authors: Keddy
authors: Michael
authors: M
authors: Mayne
authors: George S
authors: GS
authors: Robertson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D018698:Glutamic Acid / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018696:Neuroprotective Agents; D009842:Oligopeptides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D018698:Glutamic Acid; D019284:Thapsigargin; D002118:Calcium
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