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      • Abstract: found
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      STIM and ORAI proteins in the nervous system

      review-article
      Author(s): ©
      Publication date (Electronic):
      Journal: Channels
      Publisher: Taylor & Francis
      Keywords: astrocytes, capacitative calcium entry, CRAC, ORAI1, glia, microglia, neurons, STIM1, SOCE

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          Abstract

          Stromal interaction molecules (STIM) 1 and 2 are sensors of the calcium concentration in the endoplasmic reticulum. Depletion of endoplasmic reticulum calcium stores activates STIM proteins which, in turn, bind and open calcium channels in the plasma membrane formed by the proteins ORAI1, ORAI2, and ORAI3. The resulting store-operated calcium entry (SOCE), mostly controlled by the principal components STIM1 and ORAI1, has been particularly characterized in immune cells. In the nervous system, all STIM and ORAI homologs are expressed. This review summarizes current knowledge on distribution and function of STIM and ORAI proteins in central neurons and glial cells, i.e. astrocytes and microglia. STIM2 is required for SOCE in hippocampal synapses and cortical neurons, whereas STIM1 controls calcium store replenishment in cerebellar Purkinje neurons. In microglia, STIM1, STIM2, and ORAI1 regulate migration and phagocytosis. The isoforms ORAI2 and ORAI3 are candidates for SOCE channels in neurons and astrocytes, respectively. Due to the role of SOCE in neuronal and glial calcium homeostasis, dysfunction of STIM and ORAI proteins may have consequences for the development of neurodegenerative disorders, such as Alzheimer's disease.

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          A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function.

          Stefan Feske, Yousang Gwack, Murali Prakriya … (2006)
          Antigen stimulation of immune cells triggers Ca2+ entry through Ca2+ release-activated Ca2+ (CRAC) channels, promoting the immune response to pathogens by activating the transcription factor NFAT. We have previously shown that cells from patients with one form of hereditary severe combined immune deficiency (SCID) syndrome are defective in store-operated Ca2+ entry and CRAC channel function. Here we identify the genetic defect in these patients, using a combination of two unbiased genome-wide approaches: a modified linkage analysis with single-nucleotide polymorphism arrays, and a Drosophila RNA interference screen designed to identify regulators of store-operated Ca2+ entry and NFAT nuclear import. Both approaches converged on a novel protein that we call Orai1, which contains four putative transmembrane segments. The SCID patients are homozygous for a single missense mutation in ORAI1, and expression of wild-type Orai1 in SCID T cells restores store-operated Ca2+ influx and the CRAC current (I(CRAC)). We propose that Orai1 is an essential component or regulator of the CRAC channel complex.
          Article 0 comments Cited 541 times – based on 0 reviews     Review now
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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.
            Article 0 comments Cited 526 times – based on 0 reviews     Review now
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              The P2Y12 receptor regulates microglial activation by extracellular nucleotides.

              Sharon E Haynes, Gunther Hollopeter, Guang Yang … (2006)
              Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
              Article 0 comments Cited 481 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (nlm-ta): Channels (Austin)
                Journal ID (iso-abbrev): Channels (Austin)
                Journal ID (pmc): KCHL
                Title: Channels
                Publisher: Taylor & Francis
                ISSN (Print): 1933-6950
                ISSN (Electronic): 1933-6969
                Publication date Collection: Sep-Oct 2015
                Publication date (Electronic): 28 July 2015
                Publication date PMC-release: 28 July 2015
                Volume: 9
                Issue: 5
                Pages: 245-252
                Affiliations
                Carl-Ludwig-Institute for Physiology, University of Leipzig ; Leipzig, Germany
                Author notes
                Correspondence to: Robert Kraft; Email: robert.kraft@ 123456medizin.uni-leipzig.de
                Article
                Publisher ID: 1071747
                DOI: 10.1080/19336950.2015.1071747
                PMC ID: 4826113
                PubMed ID: 26218135
                SO-VID: 0386f7e8-b042-4671-a9b1-eaa80d0a35bb
                Copyright © © 2015 The Author(s). Published with license by Taylor & Francis Group, LLC
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. The moral rights of the named author(s) have been asserted.

                History
                Date received : 17 June 2015
                Date revision received : 7 July 2015
                Date accepted : 7 July 2015
                Page count
                Figures: 2, Tables: 0, References: 130, Pages: 9
                Categories
                Subject: Review

                ScienceOpen disciplines: Molecular biology
                Keywords: astrocytes,capacitative calcium entry,crac,orai1,glia,microglia,neurons,stim1,soce
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: astrocytes, capacitative calcium entry, crac, orai1, glia, microglia, neurons, stim1, soce

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