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      The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress

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          Abstract

          The mouse hippocampal cell line HT22 is an excellent model for studying the consequences of endogenous oxidative stress. Addition of extracellular glutamate depletes the cells of glutathione (GSH) by blocking the glutamate−cystine antiporter system x c −. GSH is the main antioxidant in neurons and its depletion induces a well-defined program of cell death called oxytosis, which is probably synonymous with the iron-dependent form of non-apoptotic cell death termed ferroptosis. Oxytosis is characterized by an increase of reactive oxygen species and a strong calcium influx preceding cell death. We found a significant reduction in store-operated calcium entry (SOCE) in glutamate-resistant HT22 cells caused by downregulation of the Ca 2+ channel ORAI1, but not the Ca 2+ sensors STIM1 or STIM2. Pharmacological inhibition of SOCE mimicked this protection similarly to knockdown of ORAI1 by small interfering RNAs. Long-term calcium live-cell imaging after induction of the cell death program showed a specific reduction in Ca 2+-positive cells by ORAI1 knockdown. These results suggest that dysregulated Ca 2+ entry through ORAI1 mediates the detrimental Ca 2+ entry in programmed cell death induced by GSH depletion. As this detrimental Ca 2+ influx occurs late in the course of the cell death program, it might be amenable to therapeutic intervention in diseases caused by oxidative stress.

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          STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx.

          Jen Liou, Man Lyang Kim, Won Do Heo … (2005)
          Ca(2+) signaling in nonexcitable cells is typically initiated by receptor-triggered production of inositol-1,4,5-trisphosphate and the release of Ca(2+) from intracellular stores. An elusive signaling process senses the Ca(2+) store depletion and triggers the opening of plasma membrane Ca(2+) channels. The resulting sustained Ca(2+) signals are required for many physiological responses, such as T cell activation and differentiation. Here, we monitored receptor-triggered Ca(2+) signals in cells transfected with siRNAs against 2,304 human signaling proteins, and we identified two proteins required for Ca(2+)-store-depletion-mediated Ca(2+) influx, STIM1 and STIM2. These proteins have a single transmembrane region with a putative Ca(2+) binding domain in the lumen of the endoplasmic reticulum. Ca(2+) store depletion led to a rapid translocation of STIM1 into puncta that accumulated near the plasma membrane. Introducing a point mutation in the STIM1 Ca(2+) binding domain resulted in prelocalization of the protein in puncta, and this mutant failed to respond to store depletion. Our study suggests that STIM proteins function as Ca(2+) store sensors in the signaling pathway connecting Ca(2+) store depletion to Ca(2+) influx.
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            STIM1, an essential and conserved component of store-operated Ca2+ channel function

            Jack Roos, Paul J. DiGregorio, Andriy Yeromin … (2005)
            Store-operated Ca2+ (SOC) channels regulate many cellular processes, but the underlying molecular components are not well defined. Using an RNA interference (RNAi)-based screen to identify genes that alter thapsigargin (TG)-dependent Ca2+ entry, we discovered a required and conserved role of Stim in SOC influx. RNAi-mediated knockdown of Stim in Drosophila S2 cells significantly reduced TG-dependent Ca2+ entry. Patch-clamp recording revealed nearly complete suppression of the Drosophila Ca2+ release-activated Ca2+ (CRAC) current that has biophysical characteristics similar to CRAC current in human T cells. Similarly, knockdown of the human homologue STIM1 significantly reduced CRAC channel activity in Jurkat T cells. RNAi-mediated knockdown of STIM1 inhibited TG- or agonist-dependent Ca2+ entry in HEK293 or SH-SY5Y cells. Conversely, overexpression of STIM1 in HEK293 cells modestly enhanced TG-induced Ca2+ entry. We propose that STIM1, a ubiquitously expressed protein that is conserved from Drosophila to mammalian cells, plays an essential role in SOC influx and may be a common component of SOC and CRAC channels.
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              Orai1 is an essential pore subunit of the CRAC channel.

              Murali Prakriya, Stefan Feske, Yousang Gwack … (2006)
              Stimulation of immune cells causes depletion of Ca2+ from endoplasmic reticulum (ER) stores, thereby triggering sustained Ca2+ entry through store-operated Ca2+ release-activated Ca2+ (CRAC) channels, an essential signal for lymphocyte activation and proliferation. Recent evidence indicates that activation of CRAC current is initiated by STIM proteins, which sense ER Ca2+ levels through an EF-hand located in the ER lumen and relocalize upon store depletion into puncta closely associated with the plasma membrane. We and others recently identified Drosophila Orai and human Orai1 (also called TMEM142A) as critical components of store-operated Ca2+ entry downstream of STIM. Combined overexpression of Orai and Stim in Drosophila cells, or Orai1 and STIM1 in mammalian cells, leads to a marked increase in CRAC current. However, these experiments did not establish whether Orai is an essential intracellular link between STIM and the CRAC channel, an accessory protein in the plasma membrane, or an actual pore subunit. Here we show that Orai1 is a plasma membrane protein, and that CRAC channel function is sensitive to mutation of two conserved acidic residues in the transmembrane segments. E106D and E190Q substitutions in transmembrane helices 1 and 3, respectively, diminish Ca2+ influx, increase current carried by monovalent cations, and render the channel permeable to Cs+. These changes in ion selectivity provide strong evidence that Orai1 is a pore subunit of the CRAC channel.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cell Death Dis
                Journal ID (iso-abbrev): Cell Death Dis
                Title: Cell Death & Disease
                Publisher: Nature Publishing Group
                ISSN (Electronic): 2041-4889
                Publication date (Print): January 2013
                Publication date (Electronic): 24 January 2013
                Publication date PMC-release: 1 January 2013
                Volume: 4
                Issue: 1
                Page: e470
                Affiliations
                [1 ]Department of Neurology, Heinrich-Heine Universität Düsseldorf , Düsseldorf, Germany
                [2 ]Institute of Cytology St. Petersburg , St. Petersburg, Russia
                [3 ]University of Ulm, Department of Neurology , Ulm, Germany
                [4 ]Cellular Neurobiology Laboratory, Salk Institute for Biological Studies , La Jolla, CA, USA
                [5 ]Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University Medical Center Mainz, Department of Neurology , Mainz, Germany
                Author notes
                [* ]Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University Medical Center Mainz, Department of Neurology , Langenbeckstr. 1, D-55131 Mainz, Germany, Tel: +49 6131 17 2695, Fax: +49 6131 17 5967; Email: axel.methner@ 123456gmail.com
                Article
                Publisher Item ID: cddis2012216
                DOI: 10.1038/cddis.2012.216
                PMC ID: 3564003
                PubMed ID: 23348584
                SO-VID: 4cd54492-8e75-443e-ab2e-309b4c1c21c6
                Copyright © Copyright © 2013 Macmillan Publishers Limited
                License:

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                Date received : 04 October 2012
                Date revision received : 29 November 2012
                Date accepted : 06 December 2012
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Cell biology
                Keywords: oxidative stress,soce,stim1
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: oxidative stress, soce, stim1

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