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Imaging GPCR activation in real time in living animals would provide a powerful way to study their role in biology and disease. Here, we describe a mouse model that enables the bioluminescent detection of GPCR activation in real time by utilizing the clinically important GPCR, sphingosine-1-phosphate receptor 1 (S1P<jats:sub>1<\/jats:sub>). A synthetic S1P<jats:sub>1<\/jats:sub> signaling pathway, designed to report the interaction between S1P<jats:sub>1<\/jats:sub> and \u03b2-arrestin2 via the firefly split luciferase fragment complementation system, is genetically encoded in these mice. Upon receptor activation and subsequent \u03b2-arrestin2 recruitment, an active luciferase enzyme complex is produced, which can be detected by in vivo bioluminescence imaging. This imaging strategy reveals the dynamics and spatial specificity of S1P<jats:sub>1<\/jats:sub> activation in normal and pathophysiologic contexts in vivo and can be applied to other GPCRs.<\/jats:p>","DOI":"10.1038\/s41467-017-01340-7","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T20:25:41Z","timestamp":1508790341000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Bioluminescence imaging of G protein-coupled receptor activation in living mice"],"prefix":"10.1038","volume":"8","author":[{"given":"Mari","family":"Kono","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth G.","family":"Conlon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha Y.","family":"Lux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Yanagida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8355-4065","authenticated-orcid":false,"given":"Timothy","family":"Hla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0456-1270","authenticated-orcid":false,"given":"Richard L.","family":"Proia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"1340_CR1","doi-asserted-by":"publisher","DOI":"10.1093\/database\/baq018","volume":"2010","author":"B Jassal","year":"2010","unstructured":"Jassal, B. et al. 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