{"title":"Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses","quality_controlled":"1","status":"public","related_material":{"link":[{"description":"News on ISTA website","relation":"press_release","url":"https://ista.ac.at/en/news/dreaddful-mimicry/"}],"record":[{"id":"11945","relation":"part_of_dissertation","status":"public"},{"id":"11542","relation":"research_data","status":"public"}]},"oa_version":"Published Version","oa":1,"date_created":"2022-08-28T22:01:59Z","user_id":"4359f0d1-fa6c-11eb-b949-802e58b17ae8","publisher":"Springer Nature","scopus_import":"1","date_published":"2022-08-15T00:00:00Z","publication_status":"published","department":[{"_id":"SaSi"}],"abstract":[{"lang":"eng","text":"G protein-coupled receptors (GPCRs) regulate processes ranging from immune responses to neuronal signaling. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additionally, dissecting cell type-specific responses is challenging when the same GPCR is expressed on different cells within a tissue. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that bind clozapine-N-oxide and mimic a GPCR-of-interest. We show that chimeric DREADD-β2AR triggers responses comparable to β2AR on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, an immune cell capable of driving central nervous system inflammation. When dissecting microglial inflammation, we included two additional DREADD-based chimeras mimicking microglia-enriched GPR65 and GPR109A. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with high similarity to endogenous β2AR, while DREADD-GPR109A shows no impact. Our DREADD-based approach allows investigation of cell type-dependent pathways without known endogenous ligands."}],"license":"https://creativecommons.org/licenses/by/4.0/","type":"journal_article","file":[{"relation":"main_file","checksum":"191d9db0266e14a28d3a56dc7f65da84","file_name":"2022_NatComm_Schulz.pdf","creator":"cchlebak","access_level":"open_access","content_type":"application/pdf","date_updated":"2022-08-29T06:44:30Z","date_created":"2022-08-29T06:44:30Z","file_size":7317396,"file_id":"12002","success":1}],"day":"15","article_processing_charge":"No","month":"08","date_updated":"2024-02-21T12:34:51Z","pmid":1,"tmp":{"image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","short":"CC BY (4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"acknowledgement":"The authors thank the Scientific Service Units at ISTA, in particular the Molecular Biology Service of the Lab Support Facility, Imaging & Optics Facility, and the Preclinical Facility, and the Novarino group, Harald Janoviak, and Marco Benevento for sharing reagents and expertise. This research was supported by a DOC Fellowship (24979) awarded to R.S. by the Austrian Academy of Sciences.","file_date_updated":"2022-08-29T06:44:30Z","isi":1,"project":[{"_id":"267F75D8-B435-11E9-9278-68D0E5697425","name":"Modulating microglia through G protein-coupled receptor (GPCR) signaling"}],"ddc":["570"],"intvolume":"        13","volume":13,"year":"2022","acknowledged_ssus":[{"_id":"PreCl"},{"_id":"Bio"},{"_id":"LifeSc"}],"citation":{"mla":"Schulz, Rouven, et al. “Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses.” <i>Nature Communications</i>, vol. 13, 4728, Springer Nature, 2022, doi:<a href=\"https://doi.org/10.1038/s41467-022-32390-1\">10.1038/s41467-022-32390-1</a>.","ieee":"R. Schulz, M. Korkut, A. Venturino, G. Colombo, and S. Siegert, “Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses,” <i>Nature Communications</i>, vol. 13. Springer Nature, 2022.","ama":"Schulz R, Korkut M, Venturino A, Colombo G, Siegert S. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. <i>Nature Communications</i>. 2022;13. doi:<a href=\"https://doi.org/10.1038/s41467-022-32390-1\">10.1038/s41467-022-32390-1</a>","ista":"Schulz R, Korkut M, Venturino A, Colombo G, Siegert S. 2022. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. Nature Communications. 13, 4728.","apa":"Schulz, R., Korkut, M., Venturino, A., Colombo, G., &#38; Siegert, S. (2022). Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses. <i>Nature Communications</i>. Springer Nature. <a href=\"https://doi.org/10.1038/s41467-022-32390-1\">https://doi.org/10.1038/s41467-022-32390-1</a>","chicago":"Schulz, Rouven, Medina Korkut, Alessandro Venturino, Gloria Colombo, and Sandra Siegert. “Chimeric GPCRs Mimic Distinct Signaling Pathways and Modulate Microglia Responses.” <i>Nature Communications</i>. Springer Nature, 2022. <a href=\"https://doi.org/10.1038/s41467-022-32390-1\">https://doi.org/10.1038/s41467-022-32390-1</a>.","short":"R. Schulz, M. Korkut, A. Venturino, G. Colombo, S. Siegert, Nature Communications 13 (2022)."},"article_type":"original","article_number":"4728","_id":"11995","language":[{"iso":"eng"}],"publication":"Nature Communications","has_accepted_license":"1","author":[{"full_name":"Schulz, Rouven","id":"4C5E7B96-F248-11E8-B48F-1D18A9856A87","first_name":"Rouven","last_name":"Schulz","orcid":"0000-0001-5297-733X"},{"last_name":"Korkut","first_name":"Medina","full_name":"Korkut, Medina","id":"4B51CE74-F248-11E8-B48F-1D18A9856A87","orcid":"0000-0003-4309-2251"},{"orcid":"0000-0003-2356-9403","full_name":"Venturino, Alessandro","id":"41CB84B2-F248-11E8-B48F-1D18A9856A87","first_name":"Alessandro","last_name":"Venturino"},{"orcid":"0000-0001-9434-8902","full_name":"Colombo, Gloria","id":"3483CF6C-F248-11E8-B48F-1D18A9856A87","first_name":"Gloria","last_name":"Colombo"},{"full_name":"Siegert, Sandra","id":"36ACD32E-F248-11E8-B48F-1D18A9856A87","last_name":"Siegert","first_name":"Sandra","orcid":"0000-0001-8635-0877"}],"doi":"10.1038/s41467-022-32390-1","external_id":{"isi":["000840984400032"],"pmid":["35970889"]},"publication_identifier":{"eissn":["2041-1723"]}}