{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:49:58Z","timestamp":1792014598944,"version":"4.4.0"},"reference-count":71,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001061","name":"Rebecca L. Cooper Medical Research Foundation","doi-asserted-by":"publisher","award":["PG2020710"],"award-info":[{"award-number":["PG2020710"]}],"id":[{"id":"10.13039\/501100001061","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Microglial cells, the resident immune cells of the central nervous system (CNS), are essential for maintaining CNS homeostasis. Dysregulation of microglial function is implicated in the pathogenesis of various neurodegenerative diseases. Vasoactive intestinal polypeptide receptors 1 and 2 (VPAC1 and VPAC2) are G-protein-coupled receptors (GPCRs) expressed by microglia, with their primary ligands being pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP). However, the specific roles of VPAC-type receptors in microglial regulation remain poorly understood. In this study, we generated VPAC1+\/\u2212 and VPAC2+\/\u2212 BV2 microglial cell lines using CRISPR-Cas9 gene editing and conducted a series of biological and molecular assays to elucidate the functions of these receptors. Our findings demonstrated that both mutant cell lines exhibited a polarized phenotype and increased migratory activity. VPAC1+\/\u2212 cells showed enhanced survivability and baseline activation of the unfolded protein response (UPR), a protective mechanism triggered by endoplasmic reticulum (ER) stress, whereas this response appeared impaired in VPAC2+\/\u2212 cells. In contrast, under lipopolysaccharide (LPS)-induced inflammatory conditions, UPR activation was impaired in VPAC1+\/\u2212 cells but restored in VPAC2+\/\u2212 cells, resulting in improved survival of VPAC2+\/\u2212 cells, whereas VPAC1+\/\u2212 cells exhibited reduced resilience. Overall, our findings suggest that VPAC1 and VPAC2 receptors play distinct yet complementary roles in BV2 microglia. VPAC2 is critical for regulating survival, ER stress responses, and polarization under basal conditions, while VPAC1 is essential for adaptive responses to inflammatory stimuli such as LPS. These insights advance our understanding of microglial receptor signaling and may inform therapeutic strategies targeting microglial dysfunction in neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cells14110769","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T12:24:18Z","timestamp":1748003058000},"page":"769","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["VPAC1 and VPAC2 Receptor Heterozygosity Confers Distinct Biological Properties to BV2 Microglial Cells"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7656-8965","authenticated-orcid":false,"given":"Xin Ying Rachel","family":"Song","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0721-4055","authenticated-orcid":false,"given":"Margo Iris","family":"Jansen","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rubina","family":"Marzagalli","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-8890","authenticated-orcid":false,"given":"Giuseppe","family":"Musumeci","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, University of Catania, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1114-8265","authenticated-orcid":false,"given":"Velia","family":"D\u2019Agata","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Section of Anatomy, Histology and Movement Sciences, University of Catania, 95100 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7037-759X","authenticated-orcid":false,"given":"Alessandro","family":"Castorina","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/jnc.13607","article-title":"Neuroinflammation: The devil is in the details","volume":"139","author":"DiSabato","year":"2016","journal-title":"J. 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