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MOR sorting towards the lysosome results in downregulation of opioid signaling while recycling of MOR to the plasma membrane preserves signaling function. However, the mechanisms by which LENL promotes MOR recycling are unknown, and this sequence does not match any known consensus recycling motif. Here we took a functional genomics approach with a comparative genome-wide screen design to identify genes which control opioid receptor expression and downregulation. We identified 146 hits including all three subunits of the endosomal Retromer complex. We show that the LENL motif in MOR is a novel Retromer recycling motif and that LENL is a necessary, sufficient, and conserved mechanism to give MOR access to the Retromer recycling pathway and protect MOR from agonist-induced downregulation to multiple clinically relevant opioids including fentanyl and methadone.<\/jats:p>","DOI":"10.1101\/2024.12.02.626482","type":"posted-content","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T03:00:23Z","timestamp":1733194823000},"source":"Crossref","is-referenced-by-count":0,"title":["Retromer Opposes Opioid-Induced Downregulation of the Mu Opioid Receptor"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9378-8017","authenticated-orcid":false,"given":"Aleksandra","family":"Dagunts","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0373-3678","authenticated-orcid":false,"given":"Hayden","family":"Adoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5304-2640","authenticated-orcid":false,"given":"Brandon","family":"Novy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica De","family":"Maria","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7881-7502","authenticated-orcid":false,"given":"Braden T","family":"Lobingier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024120403251039000_2024.12.02.626482v1.1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.121.000453"},{"key":"2024120403251039000_2024.12.02.626482v1.2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.22-13-05769.2002"},{"key":"2024120403251039000_2024.12.02.626482v1.3","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1995.65041636.x"},{"key":"2024120403251039000_2024.12.02.626482v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.04.015"},{"key":"2024120403251039000_2024.12.02.626482v1.5","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.004747"},{"key":"2024120403251039000_2024.12.02.626482v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2006.09.006"},{"key":"2024120403251039000_2024.12.02.626482v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2019.03.010"},{"key":"2024120403251039000_2024.12.02.626482v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2501"},{"key":"2024120403251039000_2024.12.02.626482v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/bs.pmbts.2015.03.005"},{"key":"2024120403251039000_2024.12.02.626482v1.10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201512068"},{"key":"2024120403251039000_2024.12.02.626482v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2024.111170"},{"key":"2024120403251039000_2024.12.02.626482v1.12","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2011.01284.x"},{"key":"2024120403251039000_2024.12.02.626482v1.13","doi-asserted-by":"publisher","DOI":"10.1213\/01.ANE.0000152191.29311.9B"},{"key":"2024120403251039000_2024.12.02.626482v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-50971-0"},{"key":"2024120403251039000_2024.12.02.626482v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/45816"},{"key":"2024120403251039000_2024.12.02.626482v1.16","doi-asserted-by":"publisher","DOI":"10.1042\/BST20200552"},{"key":"2024120403251039000_2024.12.02.626482v1.17","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202207070"},{"key":"2024120403251039000_2024.12.02.626482v1.18","doi-asserted-by":"crossref","first-page":"3116","DOI":"10.1016\/S0021-9258(19)39742-X","article-title":"NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor","volume":"265","year":"1990","journal-title":"J. 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