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We and others have shown that mGlu\n                      <jats:sub>5<\/jats:sub>\n                      positive allosteric modulators (PAMs) are biased agonists, triggering the activation of neuroprotective pathways and promoting neuronal survival. As mGlu\n                      <jats:sub>5<\/jats:sub>\n                      biased pharmacology arises from drug\u2010induced interactions with different protein partners, in this study, we analysed the mGlu\n                      <jats:sub>5<\/jats:sub>\n                      interactome to identify novel binding partners capable of modulating receptor cell signalling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      To identify new mGlu\n                      <jats:sub>5<\/jats:sub>\n                      partners, we employed mass spectrometry, followed by co\u2010immunoprecipitation experiments, which confirmed the interaction between mGlu\n                      <jats:sub>5<\/jats:sub>\n                      and the neuronal growth regulator 1 (NEGR1), a cell adhesion molecule. We next evaluated how NEGR1 affects mGlu\n                      <jats:sub>5<\/jats:sub>\n                      cell signalling and cellular distribution using lentivirus transduction on primary neuronal cultures to knockdown NEGR1 expression. We also assessed whether NEGR1 plays a role in the neuroprotective effects of the mGlu5 PAM, VU0409551, by evaluating apoptotic cell death and neurite degeneration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      The interaction between NEGR1 and mGlu\n                      <jats:sub>5<\/jats:sub>\n                      is important for mGlu\n                      <jats:sub>5<\/jats:sub>\n                      synaptic localization and for its coupling with Homer, thereby modulating cell signalling pathways activated by mGlu\n                      <jats:sub>5<\/jats:sub>\n                      receptors. For instance, NEGR1 knockdown led to decreased mGlu\n                      <jats:sub>5<\/jats:sub>\n                      \u2010dependent activation of ERK1\/2 and reduced expression of ARC\/ARG3.1 and BDNF. Importantly, NEGR1 knockdown affected mGlu\n                      <jats:sub>5<\/jats:sub>\n                      pharmacology, as the neuroprotective effect of VU0409551 was not observed in neurons expressing low levels of NEGR1.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      These results indicate that NEGR1 is essential for mGlu\n                      <jats:sub>5<\/jats:sub>\n                      \u2010biased activation of neuroprotective cell signalling pathways and for the neuroprotective effects triggered by VU0409551.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70671","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T23:11:09Z","timestamp":1792451469000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Interaction with NEGR1 affects mGlu\n                    <sub>5<\/sub>\n                    cell signalling and the neuroprotection induced by the positive allosteric modulator VU0409551"],"prefix":"10.1111","author":[{"given":"Jennifer D. S.","family":"Guimaraes","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toniana G.","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luan A.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuele G.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther M. A.","family":"Maciel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella P.","family":"Torres","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"Assis","sequence":"additional","affiliation":[{"name":"Department of Morphology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo L.","family":"Cardozo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao P. P.","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalia C.","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Pischedda","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Di Neuroscienze\u2010Consiglio Nazionale delle Ricerche San Raffaele Scientific Park Milano  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Piccoli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Di Neuroscienze\u2010Consiglio Nazionale delle Ricerche San Raffaele Scientific Park Milano  Milano Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciene B.","family":"Vieira","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliana","family":"Alves\u2010Silva","sequence":"additional","affiliation":[{"name":"Department of Morphology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7042-9433","authenticated-orcid":false,"given":"Fabiola M.","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Immunology, ICB Universidade Federal de Minas Gerais  Belo Horizonte Minas Gerais Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70230"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70234"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.70229"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M504508200"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-23-08710.2000"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-016-0259-6"},{"key":"e_1_2_12_9_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.neuropharm.2019.107785","article-title":"A positive allosteric modulator of mGluR5 promotes neuroprotective effects in mouse models of Alzheimer's disease","volume":"160","author":"Bellozi P. 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