title: 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.
abstract: 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.
authors.affiliation: Department of Physiology & Pharmacology, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA; Research Center for Antibody-based Drug, Institute of Biomedicine and Biotechnology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, People's Republic of China. Electronic address: cf.zhang@siat.ac.cn.
authors.forename: Changfeng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Physiology & Pharmacology, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA. Electronic address: dthomas1@pacific.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Thomas
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005233:Fatty Alcohols / Q000494:pharmacology; D052139:Intracellular Calcium-Sensing Proteins; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D000071737:Stromal Interaction Molecule 1 / Q000096:biosynthesis*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D002396:Catechols; D005233:Fatty Alcohols; D052139:Intracellular Calcium-Sensing Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C572578:SARAF protein, human; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D019284:Thapsigargin; C007845:gingerol; D002118:Calcium
keywords: Calcium influx; Calcium stores; ER stress; Neuroprotection; Oxidative stress; STIM1