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Point mutations in the gene encoding IP3 receptor subtype 3 cause impairment in T-cell and B-cell immune responses via dysfunctional Ca2+ mobilization

Cellular & Molecular Immunology volume 20, pages 214–216 (2023)Cite this article

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In the current issue of this journal, Neumann et al. provide novel insights into the role of inositol-1,4,5-trisphosphate receptor subtype 3 (IP3R3) in combined immunodeficiency [1]. They show that subjects with heterozygous variants in IP3R3 have dysfunctional Ca2+ mobilization from the endoplasmic reticulum and impaired proliferation of T and B cells. These observations demonstrate that adaptive immune cells such as T and B cells are prone to defects in IP3R3-Ca2+ signaling. This highlights a new dimension to the function of IP3R3 in adaptive immune cells that was hitherto unknown.

There are three distinct receptors that bind to inositol-1,4,5-trisphosphate (IP3), namely, IP3R1, IP3R2, and IP3R3. IP3Rs have a tetrameric structure and are embedded in the endoplasmic reticulum (ER) for gated release of Ca2+ from the ER lumen into the cytoplasm. IP3Rs consist of a ligand-binding domain, regulatory domain, and channel-forming domain. IP3 binds to IP3Rs in response to signaling cascades initiated by the activation of cell-surface receptors, such as GPCRs [2]. Activation of IP3Rs by IP3 causes efflux of Ca2+ from the ER lumen into the cytoplasm. This decrease in Ca2+ in the ER lumen is sensed by stromal interaction molecule 1 (STIM-1), which is a transmembrane receptor in the ER. A low Ca2+ concentration in the ER lumen initiates a conformational change in STIM1 that causes it to associate with the plasma membrane-bound channel protein ORAI1, thus forming calcium release-activated channel (CRAC) and causing an influx of Ca2+ into the cytoplasm. Ca2+ signaling regulates various intracellular proteins, such as calmodulin-dependent kinases and the phosphatase calcineurin, that are involved in cell survival/death through the regulation of transcriptional machinery [2, 3].

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  1. These authors contributed equally: Ahmed Nadeem, Sheikh F. Ahmad.

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  1. Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia

    Ahmed Nadeem & Sheikh F. Ahmad

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  1. Ahmed Nadeem
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Correspondence to Ahmed Nadeem or Sheikh F. Ahmad.

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Nadeem, A., Ahmad, S.F. Point mutations in the gene encoding IP3 receptor subtype 3 cause impairment in T-cell and B-cell immune responses via dysfunctional Ca2+ mobilization. Cell Mol Immunol 20, 214–216 (2023). https://doi.org/10.1038/s41423-022-00938-2

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