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

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 Ca2+-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.