Stromal Interaction Molecule 1 rescues store-operated calcium entry and protects NG115-401L cells against cell death induced by endoplasmic reticulum and mitochondrial oxidative stress.

In this study we sought to investigate the hypothesis that expression of the Stromal Interaction Molecule 1 (STIM1) could provide protection against cell death induced by ER and oxidative stress. STIM1 performs an essential role in regulating store operated calcium entry (SOCE) and thereby provides an important route for replenishment of endoplasmic reticulum (ER) Ca(2+) stores. We used NG115-401L as a model neuronal cell phenotype with a predicted high susceptibility to ER stress due to SOCE deficiency and the absence of STIM1 expression. We show that STIM1 rescue vigorously re-establishes SOCE responses inducible by sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) blockers and Ca(2+)- linked receptors, producing a useful cell line with a simple STIM1/SOCE on/off switch. Surprisingly, we find that expressing STIM1 in NG115-401L cells appears to not have a significant impact on stored ER Ca(2+) levels. Yet, even though we find no evidence for an influence on ER Ca(2+) levels, we observed that provision of STIM1 function and rescue of SOCE activity produced a neuronal phenotype with significantly greater resistance to ER stress induced by SERCA blockade. Moreover, we also report that STIM1 expression, despite elevating mitochondrial reactive oxygen species, endows the NG115-401L neuronal cells with significant resistance to agents that mediate glutathione depletion and subsequent oxidative stress induced apoptosis. Our findings thus suggest that STIM1 warrants further investigation as a potential mediator of neuroprotective pathways against ER and oxidative stress.