ORAI1

Official Full Name

ORAI calcium release-activated calcium modulator 1

Organism

Homo sapiens

GeneID

84876

Background

The protein encoded by this gene is a membrane calcium channel subunit that is activated by the calcium sensor STIM1 when calcium stores are depleted. This type of channel is the primary way for calcium influx into T-cells. Defects in this gene are a cause of immune dysfunction with T-cell inactivation due to calcium entry defect type 1 (IDTICED1). [provided by RefSeq, Sep 2011]

Synonyms

IMD9; TAM2; ORAT1; CRACM1; TMEM142A;

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Detailed Information

The ORAI1 gene is located on human chromosome 12q24.31 and encodes a critical pore-forming subunit of the calcium release-activated calcium (CRAC) channel, a landmark discovery in cellular signal transduction. ORAI1 is a four-pass transmembrane protein with both N- and C-termini in the cytoplasm, assembling at the plasma membrane to form a selective calcium-conducting channel. Its discovery emerged from studies of immunodeficiency and the molecular basis of store-operated calcium entry (SOCE). ORAI1 forms the channel pore of CRAC, and its activity is strictly dependent on the endoplasmic reticulum (ER) calcium sensor STIM1. In resting cells, STIM1 remains inactive; upon ER calcium depletion, STIM1 oligomerizes and relocates near the plasma membrane, where it directly activates ORAI1, allowing extracellular calcium influx. This process, known as store-operated calcium entry, is the primary source of cytosolic calcium signals in many cell types.

Biological Significance

ORAI1-mediated SOCE is a highly conserved and fundamental mechanism for intracellular calcium signaling. Its role is especially critical in the immune system, notably in T lymphocyte activation and function. Upon T cell receptor recognition of antigens, intracellular calcium stores are released, STIM1 senses the depletion, and ORAI1 channels are activated to permit sustained calcium influx. This sustained calcium signal activates calmodulin and downstream effectors such as the phosphatase calcineurin, leading to NFAT dephosphorylation and nuclear translocation. NFAT then drives transcription of key effector genes, including interleukin-2 and interferon-γ, supporting T cell proliferation, differentiation, and immune memory formation. Thus, ORAI1 forms a central link between antigen recognition and gene expression programs in T cells.

Figure 1. Schematic representation of ORAI1-mediated SOCE in VSMC. (Shawer H, et al., 2021)

Beyond CRAC channels, ORAI1 can form arachidonic acid–regulated calcium (ARC) channels with other subunits, representing a store-independent calcium influx pathway that fine-tunes calcium signaling in specific physiological contexts. ORAI1 also functions in mast cells, B cells, skeletal muscle, neurons, and secretory epithelial cells-for example, mediating calcium transport in mammary epithelial cells critical for milk secretion.

Clinical Relevance

The clinical significance of ORAI1 was first demonstrated through human severe combined immunodeficiency (SCID) caused by ORAI1 loss-of-function mutations. These autosomal recessive mutations result in profound T cell functional defects, recurrent life-threatening infections from early childhood, autoimmunity, and non-immune abnormalities, establishing ORAI1 as indispensable for human immune system development and function.

Given its central role in T cell activation, ORAI1 is an attractive target for novel immunosuppressive therapies for autoimmune diseases and transplant rejection. Selective blockade of ORAI1 via small molecules or monoclonal antibodies can inhibit pathological T cell activation without the broad cytotoxicity associated with calcineurin inhibitors. Several pharmaceutical companies and research institutions are developing ORAI1-specific inhibitors, which have shown efficacy in animal models of autoimmune diseases such as psoriasis and rheumatoid arthritis, and some lead compounds have entered early clinical trials.

Challenges remain in balancing immune suppression with potential side effects due to ORAI1's roles in calcium signaling in skeletal muscle and the nervous system. In oncology, modulating calcium signals in the tumor microenvironment may influence tumor survival and immune cell infiltration, though translational applications are still in early exploration. Overall, ORAI1 exemplifies a discovery rapidly advancing from fundamental science to clinical validation, offering promising avenues for therapeutic intervention in autoimmune diseases.

References

Feske S, Gwack Y, Prakriya M, et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature. 2006;441(7090):179–185.
Shawer H, Norman K, Cheng CW, et al. ORAI1 Ca²⁺ Channel as a Therapeutic Target in Pathological Vascular Remodelling. Front Cell Dev Biol. 2021 Apr 6;9:653812.
Prakriya M, Feske S, Gwack Y, et al. Orai1 is an essential pore subunit of the CRAC channel. Nature. 2006;443(7108):230–233.
Vaeth M, Feske S. Ion channelopathies of the immune system. Curr Opin Immunol. 2018;52:39–50.

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