Orai1 and Orai3 in combination with stim1 mediate the majority of store-operated calcium entry in astrocytes

Jea Kwon, Heeyoung An, Moonsun Sa, Joungha Won, Jeong Im Shin, C. Justin Lee

    Research output: Contribution to journalArticlepeer-review

    47 Citations (Scopus)

    Abstract

    Astrocytes are non-excitable cells in the brain and their activity largely depends on the intracellular calcium (Ca2+) level. Therefore, maintaining the intracellular Ca2+ homeostasis is critical for proper functioning of astrocytes. One of the key regulatory mechanisms of Ca2+ homeostasis in astrocytes is the store-operated Ca2+ entry (SOCE). This process is mediated by a combination of the Ca2+- store-depletion-sensor, Stim, and the store-operated Ca2+-channels, Orai and TrpC families. Despite the existence of all those families in astrocytes, previous studies have provided conflicting results on the molecular identification of astrocytic SOCE. Here, using the shRNA-based gene-silencing approach and Ca2+-imaging from cultured mouse astrocytes, we report that Stim1 in combination with Orai1 and Orai3 contribute to the major portion of astrocytic SOCE. Gene-silencing of Stim1 showed a 79.2% reduction of SOCE, indicating that Stim1 is the major Ca2+-store-depletion-sensor. Further gene-silencing showed that Orai1, Orai2, Orai3, and TrpC1 contribute to SOCE by 35.7%, 20.3%, 26.8% and 12.2%, respectively. Simultaneous gene-silencing of all three Orai subtypes exhibited a 67.6% reduction of SOCE. Based on the detailed population analysis, we predict that Orai1 and Orai3 are expressed in astrocytes with a large SOCE, whereas TrpC1 is exclusively expressed in astrocytes with a small SOCE. This analytical approach allows us to identify the store operated channel (SOC) subtype in each cell by the degree of SOCE. Our results propose that Stim1 in combination with Orai1 and Orai3 are the major molecular components of astrocytic SOCE under various physiological and pathological conditions.

    Original languageEnglish
    Pages (from-to)42-54
    Number of pages13
    JournalExperimental Neurobiology
    Volume26
    Issue number1
    DOIs
    Publication statusPublished - 2017

    Bibliographical note

    Publisher Copyright:
    © Experimental Neurobiology 2017.

    Keywords

    • Astrocyte
    • Orai1
    • Orai3
    • SOCE
    • Stim1
    • TrpC1

    ASJC Scopus subject areas

    • Clinical Neurology
    • Cellular and Molecular Neuroscience

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