{
  "abstract": "The Ca2+ release-activated Ca2+ (CRAC) channel mediates store-operated calcium entry (SOCE), a ubiquitous pathway essential for many cell types, including immune cells. Three Orai (Orai1, Orai2, Orai3) proteins constitute the plasma membrane pore-forming units of CRAC channels that are activated by the endoplasmic reticulum (ER) Ca2+-sensing STIM1 and STIM2 proteins when ER Ca2+ stores are depleted. Orai1/2/3 are differentially expressed across primary cells with discernible differences in their structures and biophysical properties. Further, Orai1 has two alternatively translated isoforms: the long mammalian-specific Orai1alpha and the 63-residue shorter Orai1beta, which is evolutionarily older and conserved across vertebrates. Whether Orai1alpha/1beta/2/3 at native expression levels produce unique cytosolic Ca2+ signatures that bias transcriptional responses through effectors like NFAT is unclear. Here we used HEK293 cells engineered to express one native Orai isoform and show that all Orai isoforms couple to NFAT1 and NFAT4 induction. The magnitude of NFAT1/4 induction tracked the magnitude of SOCE, with the following profile: Orai1alpha>Orai1beta>>Orai2>Orai3. Near-native ectopic expression of either Orai1alpha or Orai1beta in primary murine Orai1-/-CD4+ T cells restored SOCE, NFAT activation, cytokine production and promoted near identical transcriptional responses enriched for immune activation pathways. An analysis of genetic and clinical data of human individuals showed that homozygous null mutations selectively abolishing Orai1alphaare not associated with disease resembling CRAC channelopathy. Primary T cells from individuals homozygous or heterozygous for an Orai1alpha null mutation showed enhanced, rather than impaired, SOCE and NFAT induction. Collectively, our data indicate that Orai isoforms regulate NFAT activation and downstream transcription primarily through the magnitude of SOCE they support, with Orai1alpha and Orai1beta being the most potent isoforms coupling SOCE to NFAT responses.",
  "abstract_shown": true,
  "affiliations": [
    "University of Pittsburgh"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 23,
  "authors": [
    {
      "name": "A. E. Abdelnaby"
    },
    {
      "name": "Y.-H. Wang"
    },
    {
      "name": "C. J. Benson"
    },
    {
      "name": "I. P. Perez"
    },
    {
      "name": "B. Shen"
    },
    {
      "name": "M. McDermott"
    },
    {
      "name": "M. Jishage"
    },
    {
      "name": "A. T. Elhaw"
    },
    {
      "name": "S. Cruz-Rangel"
    },
    {
      "name": "R. Courjaret"
    },
    {
      "name": "A. Belkadi"
    },
    {
      "name": "F. Yu"
    },
    {
      "name": "D. Prado"
    },
    {
      "name": "S. Yuan"
    },
    {
      "name": "P. Xin"
    },
    {
      "name": "A. C. Straub"
    },
    {
      "name": "F. J. Schopfer"
    },
    {
      "name": "N. Hempel"
    },
    {
      "name": "W. Hawse"
    },
    {
      "name": "D. Beck"
    },
    {
      "name": "K. Machaca"
    },
    {
      "name": "S. Feske"
    },
    {
      "affs": [
        0
      ],
      "name": "M. Trebak"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7nw3wdvbnsbpw.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.07.10.737753",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.07.10.737753v2.full",
  "id": "7nw3wdvbnsbpw",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.07.10.737753v2",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cell biology"
    ],
    [
      "openalex",
      "2809|Ion Channels and Receptors"
    ]
  ],
  "openalex": "W7168221703",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.07.10.737753v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-07-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7nw3wdvbnsbpw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:21Z",
      "native_id": "10.64898/2026.07.10.737753",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.07.10.737753v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Orai1α and Orai1β more potently promote NFAT activation and transcription than Orai2 and Orai3",
  "title_text": "Orai1α and Orai1β more potently promote NFAT activation and transcription than Orai2 and Orai3",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:21Z",
  "url": "https://research.draconitic.com/paper/7nw3wdvbnsbpw",
  "venue": "bioRxiv",
  "versions": []
}