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As the field strives to increase the use of physiological cell types with endogenous receptor expression, enhancing the sensitivity of simple-to-use assays unlocks new screening modalities. Here, we enhanced the responsivity of a Nuclear Factor of Activated T cells response element (NFAT-RE) reporter, by concatenating the IL-2 promoter-derived triplicate-binding sites, to produce three nano-luciferase reporter constructs termed NFAT 2X, NFAT 3X and NFAT 4X. Our enhanced reporters demonstrate larger maximal Fold Induction (FI) when co-expressed with both primarily and secondarily G\u03b1\n                    <jats:sub>q\/11<\/jats:sub>\n                    -coupled GPCRs. This pattern was maintained when stimulating endogenous GPCRs in a panel of immortalised cell lines (HEK293, HeLa, A549, and HEK293T) and allowed us to observe Sphingosine-1-Phosphate (S1P)-mediated signalling in primary human CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells via CRISPR\/Cas9 knock-in. Our NFAT-reporter T cells demonstrate the reporters potential for use in bi-allelic expression systems and primary cell types.\n                  <\/jats:p>","DOI":"10.1038\/s42003-026-10110-5","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T23:46:01Z","timestamp":1777160761000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Enhancement of a nuclear factor of activated T cells (NFAT) reporter for the study of G protein-coupled receptors"],"prefix":"10.1038","volume":"9","author":[{"given":"Edward","family":"Wills","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0775-690X","authenticated-orcid":false,"given":"Anjana","family":"Saji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Sumner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2760-1490","authenticated-orcid":false,"given":"Aman","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-4294-0417","authenticated-orcid":false,"given":"Claudia M.","family":"Sisk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Shehata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6101-3786","authenticated-orcid":false,"given":"Benjamin","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7320-9612","authenticated-orcid":false,"given":"Graham","family":"Ladds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,26]]},"reference":[{"key":"10110_CR1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1016\/j.cell.2024.11.036","volume":"188","author":"MK Howard","year":"2025","unstructured":"Howard, M. 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