{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:15:31Z","timestamp":1790381731729,"version":"4.1.0"},"reference-count":46,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2022,8,2]],"date-time":"2022-08-02T00:00:00Z","timestamp":1659398400000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,2,8]]},"abstract":"<jats:p>\n                    G protein\u2013coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR\n                    <jats:sub>2<\/jats:sub>\n                    ) in colitis. To localize PAR\n                    <jats:sub>2<\/jats:sub>\n                    and assess redistribution during disease, we generated knockin mice expressing PAR\n                    <jats:sub>2<\/jats:sub>\n                    fused to monomeric ultrastable green fluorescent protein (muGFP). PAR\n                    <jats:sub>2<\/jats:sub>\n                    -muGFP signaled and trafficked normally. PAR\n                    <jats:sub>2<\/jats:sub>\n                    messenger RNA was detected at similar levels in\n                    <jats:italic>\n                      Par\n                      <jats:sub>2<\/jats:sub>\n                      -mugfp\n                    <\/jats:italic>\n                    and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using\n                    <jats:italic>F2rl1<\/jats:italic>\n                    (PAR\n                    <jats:sub>2<\/jats:sub>\n                    ) and\n                    <jats:italic>Gfp<\/jats:italic>\n                    probes revealed that PAR\n                    <jats:sub>2<\/jats:sub>\n                    -muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR\n                    <jats:sub>2<\/jats:sub>\n                    -muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR\n                    <jats:sub>2<\/jats:sub>\n                    -muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR\n                    <jats:sub>2<\/jats:sub>\n                    . PAR\n                    <jats:sub>2<\/jats:sub>\n                    agonists stimulated endocytosis of PAR\n                    <jats:sub>2<\/jats:sub>\n                    and recruitment of G\u03b1\n                    <jats:sub>q<\/jats:sub>\n                    , G\u03b1\n                    <jats:sub>i<\/jats:sub>\n                    , and \u03b2-arrestin to early endosomes of T84 colon carcinoma cells. PAR\n                    <jats:sub>2<\/jats:sub>\n                    agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (\n                    <jats:italic>Dnm2<\/jats:italic>\n                    ), the major colonocyte isoform, and Dnm inhibition attenuated PAR\n                    <jats:sub>2<\/jats:sub>\n                    endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR\n                    <jats:sub>2<\/jats:sub>\n                    endocytosis sustains protease-evoked inflammation and nociception and PAR\n                    <jats:sub>2<\/jats:sub>\n                    in endosomes is a potential therapeutic target for colitis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2112059119","type":"journal-article","created":{"date-parts":[[2022,2,2]],"date-time":"2022-02-02T15:45:13Z","timestamp":1643816713000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":50,"title":["Mice expressing fluorescent PAR\n                    <sub>2<\/sub>\n                    reveal that endocytosis mediates colonic inflammation and pain"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2737-8233","authenticated-orcid":false,"given":"Rocco","family":"Latorre","sequence":"first","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Hegron","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe J.","family":"Peach","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1045-0879","authenticated-orcid":false,"given":"Shavonne","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2175-9804","authenticated-orcid":false,"given":"Raquel","family":"Tonello","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4984-4530","authenticated-orcid":false,"given":"Jeffri S.","family":"Retamal","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0347-3543","authenticated-orcid":false,"given":"Rafael","family":"Klein-Cloud","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Bok","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6540-2375","authenticated-orcid":false,"given":"Dane D.","family":"Jensen","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Gottesman-Katz","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette","family":"Rientjes","sequence":"additional","affiliation":[{"name":"Gene Modification Platform, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8902-9365","authenticated-orcid":false,"given":"Nicholas A.","family":"Veldhuis","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, 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B.","family":"Thomsen","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, NY 10010"},{"name":"Bluestone Center for Clinical Research, New York University College of Dentistry, New York, NY 10010"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charalabos H.","family":"Pothoulakis","sequence":"additional","affiliation":[{"name":"Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, CA 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