{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nS1P receptor 5 (S1P5), sometimes denoted as Edg8, is a member of the G‐protein coupled family that mediates signaling in response to the lipid mediator sphingosine 1‐phosphate (S1P). Early characterization studies established that S1P5 couples to G(i/o) proteins to regulate intracellular signaling cascades, including inhibition of adenylyl cyclase and activation of GTP‐binding, as well as modulating downstream effectors. These early findings also underscored that phosphorylation of pro‐drugs (e.g., FTY720) can yield potent agonists at multiple S1P receptors including S1P5."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin the central nervous system, S1P5 expression is largely restricted to oligodendrocytes. In immature pre‐oligodendrocytes, activation of S1P5 triggers process retraction via Rho kinase and related signaling pathways, whereas in mature myelin-forming oligodendrocytes, its activation instead promotes cell survival through a pertussis toxin–and Akt-dependent mechanism. These developmental stage–specific responses underscore a critical role for S1P5 in neural differentiation and maintenance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the immune system, S1P5 has emerged as a key regulator of cell egress and trafficking. Its expression—induced by transcription factors such as T-bet—is essential for natural killer (NK) cells to exit lymph nodes and bone marrow, a process not inhibited by CD69 and thus particularly suited for mobilizing activated cells to effector sites. In parallel, patrolling Ly6C(–) monocytes depend on S1P5 to exit the bone marrow, highlighting its role in immune surveillance and inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTissue-resident memory T (TRM) cells also exhibit a distinct interplay with S1P5 signaling. Downregulation of S1P5 in these cells is a critical step for their local retention within peripheral tissues, as forced sustained expression hampers their residency. This regulatory axis, involving transcription factors such as T-bet and ZEB2 along with modulation by local TGF-β signals, illustrates how S1P5 expression is finely tuned to balance tissue egress with immune protection."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in mature immune and neural cells, S1P5 also contributes to early signaling events in non-differentiated cells. In embryonic stem cells, stimulation with a selective S1P5 agonist promotes ERK1/2 activation via a mechanism involving G(i)-, PKC-, and c-Src–dependent pathways. Importantly, in neurodegenerative contexts such as Huntington's disease, selective pharmacological activation of S1P5 has been shown to trigger pro-survival pathways (including BDNF, AKT, and ERK), reduce mutant protein aggregation, and preserve blood–brain barrier integrity, thereby slowing disease progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies integrating chemokine receptor signaling with S1P receptor responses have underscored that distinct S1P receptor subtypes mediate specialized migratory functions. While work on transcriptional regulators such as KLF2 emphasizes the role of related receptors like S1P1 in T cell trafficking, the specific contributions of S1P5 in guiding cell egress and tissue infiltration highlight a unique functional niche among the S1P receptor family."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "D S Im, J Clemens, T L Macdonald, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of the human and mouse sphingosine 1-phosphate receptor, S1P5 (Edg-8): structure-activity relationship of sphingosine1-phosphate receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2001)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi011606i"}], "href": "https://doi.org/10.1021/bi011606i"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11705398"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11705398"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Volker Brinkmann, Michael D Davis, Christopher E Heise, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The immune modulator FTY720 targets sphingosine 1-phosphate receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C200176200"}], "href": "https://doi.org/10.1074/jbc.C200176200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11967257"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11967257"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "C Jaillard, S Harrison, B Stankoff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.4645-04.2005"}], "href": "https://doi.org/10.1523/JNEUROSCI.4645-04.2005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15703400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15703400"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Craig N Jenne, Anselm Enders, Richard Rivera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20090525"}], "href": "https://doi.org/10.1084/jem.20090525"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19808259"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19808259"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Katia Mayol, Vincent Biajoux, Jacqueline Marvel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sequential desensitization of CXCR4 and S1P5 controls natural killer cell trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2011-06-362574"}], "href": "https://doi.org/10.1182/blood-2011-06-362574"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21911833"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21911833"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Emilie Debien, Katia Mayol, Vincent Biajoux, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S1PR5 is pivotal for the homeostasis of patrolling monocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201343312"}], "href": "https://doi.org/10.1002/eji.201343312"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23519784"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23519784"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Maximilien Evrard, Erica Wynne-Jones, Changwei Peng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20210116"}], "href": "https://doi.org/10.1084/jem.20210116"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34677611"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34677611"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Alayna Rodgers, David Mormeneo, Jaclyn S Long, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine 1-phosphate regulation of extracellular signal-regulated kinase-1/2 in embryonic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells Dev (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/scd.2009.0023"}], "href": "https://doi.org/10.1089/scd.2009.0023"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19228106"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19228106"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Alba Di Pardo, Salvatore Castaldo, Enrico Amico, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Stimulation of S1PR5 with A-971432, a selective agonist, preserves blood-brain barrier integrity and exerts therapeutic effect in an animal model of Huntington's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddy153"}], "href": "https://doi.org/10.1093/hmg/ddy153"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29688337"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29688337"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Adam C Yopp, Jordi C Ochando, Minwei Mao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine 1-phosphate receptors regulate chemokine-driven transendothelial migration of lymph node but not splenic T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.175.5.2913"}], "href": "https://doi.org/10.4049/jimmunol.175.5.2913"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16116177"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16116177"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Ailin Bai, Hui Hu, Mandy Yeung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.178.12.7632"}], "href": "https://doi.org/10.4049/jimmunol.178.12.7632"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17548599"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17548599"}]}]}]}